bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2022‒12‒18
sixteen papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research
  1. Binding of active Ras and its mutants to the Ras binding domain of PI-3-kinase: A quantitative approach to KD measurements.
  2. RAS Drives Malignancy through Altered Stem Cell/Microenvironment Cross-talk.
  3. Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer.
  4. Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis.
  5. Identification of BIK as an unfavorable prognostic marker and novel therapeutic target in microsatellite stable colorectal cancer harboring KRAS mutations.
  6. ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation.
  7. Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1.
  8. BAF53A drives colorectal cancer development by regulating DUSP5-mediated ERK phosphorylation.
  9. Genetic and epigenetic characteristics of patients with colorectal cancer from Uruguay.
  10. Silencing effects of mutant RAS signalling on transcriptomes.
  11. Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions.
  12. Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function.
  13. AKT1 phosphorylates RBM17 to promote Sox2 transcription by modulating alternative splicing of FOXM1 to enhance cancer stem cell properties in colorectal cancer cells.
  14. mTORC2 inhibition improves morphological effects of PTEN loss, but does not correct synaptic dysfunction or prevent seizures.
  15. Upregulation of PIK3IP1 monitors the anti-cancer activity of PI3Kα inhibitors in gastric cancer cells.
  16. NDRG1 in Cancer: A Suppressor, Promoter, or Both?
  1. Anal Biochem. 2022 Dec 13. pii: S0003-2697(22)00479-1. [Epub ahead of print] 115019
    Binding of active Ras and its mutants to the Ras binding domain of PI-3-kinase: A quantitative approach to KD measurements.
    Ian Fleming, Jonathan P Hannan, George Hayden Swisher, Corey D Tesdahl, Justin G Martyr, Nicholas J Cordaro, Annette H Erbse, Joseph J Falke.
      Ras family GTPases (H/K/N-Ras) modulate numerous effectors, including the lipid kinase PI3K (phosphatidylinositol-3-kinase) that generates growth signal lipid PIP3 (phosphatidylinositol-3,4,5-triphosphate). Active GTP-Ras binds PI3K with high affinity, thereby stimulating PIP3 production. We hypothesize the affinity of this binding interaction could be significantly increased or decreased by Ras mutations at PI3K contact positions, with clinical implications since some Ras mutations at PI3K contact positions are disease-linked. To enable tests of this hypothesis, we have developed an approach combining UV spectral deconvolution, HPLC, and microscale thermophoresis to quantify the KD for binding. The approach measures the total Ras concentration, the fraction of Ras in the active state, and the affinity of active Ras binding to its docking site on PI3K Ras binding domain (RBD) in solution. The approach is illustrated by KD measurements for the binding of active H-Ras and representative mutants, each loaded with GTP or GMPPNP, to PI3Kγ RBD. The findings demonstrate that quantitation of the Ras activation state increases the precision of KD measurements, while also revealing that Ras mutations can increase (Q25L), decrease (D38E, Y40C), or have no effect (G13R) on PI3K binding affinity. Significant Ras affinity changes are predicted to alter PI3K regulation and PIP3 growth signals.
    Keywords:  GMPPN; GMPPNP; GTP; HRas GTPase; Protein-nucleotide complex; Ras small G protein
    DOI:  https://doi.org/10.1016/j.ab.2022.115019
  2. Cancer Discov. 2022 Dec 16. OF1
    RAS Drives Malignancy through Altered Stem Cell/Microenvironment Cross-talk.
      Oncogenic RAS promotes malignant progression by altering stem cell cross-talk with the microenvironment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-217
  3. Front Oncol. 2022 ;12 1055019
    Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer.
    Daniele Lavacchi, Sara Fancelli, Giandomenico Roviello, Francesca Castiglione, Enrico Caliman, Gemma Rossi, Jacopo Venturini, Elisa Pellegrini, Marco Brugia, Agnese Vannini, Caterina Bartoli, Fabio Cianchi, Serena Pillozzi, Lorenzo Antonuzzo.
      Background: About half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs.Methods: Data from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA.
    Results: Among 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p=0.005) and male sex (1-sided p=0.039), KRAS G12C mutation with peritoneal metastases (1-sided p=0.035), KRAS G12V mutation with female sex (1-sided p=0.025) and no surgery for primary tumor (1-sided p=0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases.Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months; HR 0.45 [0.21-0.99], p=0.04). No difference in survival was observed for mutations at codon 12/13/61 (p=0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p=0.036) and mOS (p=0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p=0.031).
    Conclusions: Patterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs.
    Keywords:  Exon 4; G12C; G12V; KRAS; bevacizumab; codon 117; codon 146; colorectal cancer
    DOI:  https://doi.org/10.3389/fonc.2022.1055019
  4. J Biol Chem. 2022 Dec 09. pii: S0021-9258(22)01231-5. [Epub ahead of print] 102788
    Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis.
    Pranetha Baskaran, Simeon R Mihaylov, Elin Vinsland, Kriti Shah, Lucy Granat, Sila K Ultanir, Andrew R Tee, Jernej Murn, Joseph M Bateman.
      Mechanistic target of rapamycin (mTOR) is a protein kinase that integrates multiple inputs to regulate anabolic cellular processes. For example , mTOR complex I (mTORC1) has key functions in growth control, autophagy and metabolism. However, much less is known about the signaling components that act downstream of mTORC1 to regulate cellular morphogenesis. Here we show that the RNA-binding protein Unkempt, a key regulator of cellular morphogenesis, is a novel substrate of mTORC1. We show that Unkempt phosphorylation is regulated by nutrient levels and growth factors via mTORC1. To analyze Unkempt phosphorylation, we immunoprecipitated Unkempt from cells in the presence or absence of the mTORC1 inhibitor rapamycin and used mass spectrometry to identify mTORC1-dependent phosphorylated residues. This analysis showed that mTORC1-dependent phosphorylation is concentrated in a serine-rich intrinsically disordered region in the C-terminal half of Unkempt. We also found that Unkempt physically interacts with and is directly phosphorylated by mTORC1 through binding to the regulatory-associated protein of mTOR, Raptor. Furthermore, analysis in the developing brain of mice lacking TSC1 expression showed that phosphorylation of Unkempt is mTORC1-dependent in vivo. Finally, mutation analysis of key serine/threonine residues in the serine-rich region indicates that phosphorylation inhibits the ability of Unkempt to induce a bipolar morphology. Phosphorylation within this serine-rich region thus profoundly affects the ability of Unkempt to regulate cellular morphogenesis. Taken together, our findings reveal a novel molecular link between mTORC1 signaling and cellular morphogenesis.
    Keywords:  Raptor; Unkempt; cellular morphogenesis; intrinsically disordered region; mTOR; phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102788
  5. Am J Cancer Res. 2022 ;12(11): 5300-5314
    Identification of BIK as an unfavorable prognostic marker and novel therapeutic target in microsatellite stable colorectal cancer harboring KRAS mutations.
    Peng Liu, Feng Jiao, Zhenghua Zhang, Feilong Zhao, Jinping Cai, Shiqing Chen, Tao Fu, Min Li.
      KRAS mutations lead to persistent activation of multiple downstream effectors that drive the cancer phenotype. Approximately 30%-50% of colorectal cancer (CRC) patients harbor KRAS mutations, which confer more aggressive tumor biology and shorter overall survival (OS), especially in microsatellite stable (MSS) metastatic CRC. Given that KRAS mutant protein has been proven difficult to target directly, identifying genes that function closely with KRAS and targeting these genes seems to be a promising therapeutic strategy for KRAS-mutated MSS CRC. Here, KRAS function-sensitive genes were identified by assessing the correlation between gene dependency scores from CRISPR knockout screens and KRAS mRNA expression in KRAS-mutated MSS CRC cell lines in the Cancer Cell Line Encyclopedia (CCLE) database. If the correlation coefficient was ≥ 0.6, the gene was considered a KRAS function-sensitive gene. Then KRAS function-sensitive genes related to prognosis were screened out in The Cancer Genome Atlas (TCGA) cohort, and the prognostic value was validated in the Gene Expression Omnibus (GEO) cohort. Single-sample gene set enrichment analysis (ssGSEA) was performed to investigate the potential mechanisms. PockDrug-Server was used to predict the druggability of candidate genes. The results showed that in 20 KRAS-mutated MSS CRC cell lines, 13 genes were identified as KRAS function-sensitive genes. Of these 13 genes, only BIK expression was significantly associated with progression-free survival (PFS) and OS, and the BIK-high patients had significantly poorer PFS (HR=3.18, P=0.020) and OS (HR=4.74, P=0.030) than the BIK-low patients. Multivariate Cox regression analysis revealed high BIK expression as an independent predictor for poorer prognosis in KRAS-mutated MSS CRC. The prognostic value of BIK was also successfully validated in a GEO cohort. The results of ssGSEA showed that the BIK-high group was more prone to strong metastasis activity than the BIK-low group. Pocket druggability prediction analysis presented that BIK had three druggable pockets, and their druggability scores were above 0.8. These findings suggested that BIK is a promising prognostic marker and therapeutic target in KRAS-mutated MSS CRC.
    Keywords:  BIK; Colorectal cancer; KRAS function-sensitive genes; KRAS mutations; microsatellite stable
  6. Front Oncol. 2022 ;12 1043177
    ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation.
    Daqi Jia, Leilei Li, Peng Wang, Qiang Feng, Xinyan Pan, Peng Lin, Shuling Song, Lilin Yang, Julun Yang.
      Background: Clinical treatment of RAS mutant cancers is challenging because of the complexity of the Ras signaling pathway. SLC7A5 is a newly discovered downstream gene of the Ras signaling pathway, but the regulatory mechanism is unclear. We aimed to explore the molecular mechanism and role in KRAS mutant lung adenocarcinoma progression.Methods: Key gene that regulated SLC7A5 in KRAS mutant lung adenocarcinoma was screened by RNA sequencing and bioinformatics analysis. The effect of this gene on the expression of SLC7A5 was studied by RNAi. The regulatory mechanism between the two genes was investigated by immunofluorescence, CoIP, pulldown and yeast two-hybrid assays. The location of the two genes was determined by inhibiting Ras and the downstream pathways PI3K-AKT and MEK-ERK. By in vivo and in vitro experiments, the effects of the key gene on the biological functions of KRAS mutant lung adenocarcinoma were explored.
    Results: We found a novel gene, ZNF24, which upregulated SLC7A5 protein expression rather than mRNA expression in KRAS mutant lung adenocarcinoma. Endogenous protein interactions occurred between ZNF24 and SLC7A5. Ras inhibition reduced the expression of ZNF24 and SLC7A5. ZNF24 and SLC7A5 are located downstream of the MEK-ERK and PI3K-AKT pathways. In vivo and in vitro functional experiments confirmed that the ZNF24-SLC7A5 signaling axis promoted the proliferation, invasion and migration of KRAS mutant lung adenocarcinoma.
    Conclusions: ZNF24 promoted the growth of KRAS mutant lung adenocarcinoma by upregulating SLC7A5 protein expression, which suggested that ZNF24 is a new biomarker of KRAS mutant tumors and could be a new potential therapeutic target for Ras-driven tumors.
    Keywords:  KRAS mutation; SLC7A5; ZNF24; lung adenocarcinoma; protein interaction
    DOI:  https://doi.org/10.3389/fonc.2022.1043177
  7. Cancer Res Commun. 2022 Sep;2(9): 1061-1074
    Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1.
    Richard Kurupi, Konstantinos V Floros, Sheeba Jacob, Ayesha T Chawla, Jinyang Cai, Bin Hu, Madhavi Puchalapalli, Colin M Coon, Rishabh Khatri, Giovanna Stein Crowther, Regina K Egan, Ellen Murchie, Patricia Greninger, Krista M Dalton, Maninderjit S Ghotra, Sosipatros A Boikos, Jennifer E Koblinski, Hisashi Harada, Yue Sun, Iain M Morgan, Devraj Basu, Mikhail G Dozmorov, Cyril H Benes, Anthony C Faber.
      Preclinical and clinical studies have evidenced that effective targeted therapy treatment against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, re-activation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found HNSCC was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCC, resulting in downregulation of mTORC signaling and anti-tumor effects across several HNSCC mouse models, including an HPV+ patient-derived xenograft (PDX). Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2-GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. We demonstrate HNSCCs were highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin.
    Keywords:  Epiregulin; Head and neck squamous cell carcinoma; SHP099; SHP2; Targeted therapy
    DOI:  https://doi.org/10.1158/2767-9764.crc-21-0137
  8. Cell Death Dis. 2022 Dec 16. 13(12): 1049
    BAF53A drives colorectal cancer development by regulating DUSP5-mediated ERK phosphorylation.
    Ziqing Yang, Dandan Huang, Manqi Meng, Wencong Wang, Junyan Feng, Lekun Fang, Honglei Chen, Shaomin Zou.
      BAF53A, an important subunit of the SWI/SNF epigenetic chromatin regulatory complex, has been implicated as the driver of diverse cancers. However, the role of BAF53A in colorectal cancer (CRC) remains poorly understood. Here, we examined the expression of BAF53A in CRC samples and observed that BAF53A was significantly upregulated in CRC tissues compared with paired adjacent normal tissues. In vitro and in vivo studies suggested that ectopic expression of BAF53A promoted colorectal cancer cell proliferation, colony formation, and tumorigenesis, whereas knockdown of BAF53A hindered these cellular functions. DUSP5 (dual-specificity phosphatase 5), an ERK1/2-specific endogenous phosphatase, was expressed at low levels in CRC. We found a negative correlation between BAF53A and DUSP5 expression in a set of CRC samples. Mechanistic studies revealed that P63 was a potential transcription repressor of DUSP5. BAF53A could interact with P63, decreasing the DUSP5 expression level and subsequently promoting ERK1/2 phosphorylation. Thus, our study provides insights into the applicability of the BAF53A-DUSP5-ERK1/2 axis as a potential therapeutic target in CRC.
    DOI:  https://doi.org/10.1038/s41419-022-05499-w
  9. Pathol Res Pract. 2022 Dec 06. pii: S0344-0338(22)00508-8. [Epub ahead of print]241 154264
    Genetic and epigenetic characteristics of patients with colorectal cancer from Uruguay.
    Marcelo Vital, Florencia Carusso, Carolina Vergara, Florencia Neffa, Adriana Della Valle, Patricia Esperón.
      Colorectal cancer (CRC), the 3rd most frequent cancer worldwide, affects both men and women. This pathology arises from the progressive accumulation of genetic and epigenetic alterations. In this study, KRAS, NRAS, PIK3CA, and BRAF gene mutations, mismatch repair (MMR) genes methylation profile, microsatellite instability (MSI) and CpG Island Methylator Phenotype (CIMP) status were assessed. The associations of these molecular features with clinicopathological data were also investigated. A hundred and eight unselected CRC samples and their histological and clinical data, were gathered between 2017 and 2020. The prevalence of KRAS, NRAS and BRAF gene mutations was similar to that described in other populations. 28.7% of tumors were KRAS-mutated, mostly in men, distal location, with a CIMP-negative status. BRAFV600E frequency was 6.5% and associated with MSI (p = 0.048), MLH1-methylated (p < 0.001) and CIMP-High (p < 0.001) status. We also confirmed that BRAFV600E tumors were more prevalent in older women and proximal location. A striking different result was the lack of most common variants in the PIK3CA gene. A complete absence of PIK3CA-mutated tumors in a population has not been previously reported. Among MMR genes, the only with an aberrant methylation pattern was MLH1 gene. Its frequency was 9.25%, lower than previously reported. Methylated tumors were most frequent in patients older than 70 years old and proximal tumor location. Finally, CIMP-High status was mainly observed in moderately differentiated tumors with a rate of 15.7%. Our findings were consistent with previous reports in other populations, but also showed some features unique to our cohort. This study is the first to report the analysis of a large number molecular biomarkers of CRC in Uruguay and one of the few performed in Latin-America.
    Keywords:  BRAF; Colorectal cancer; Epigenetics; KRAS; NRAS; PIK3CA
    DOI:  https://doi.org/10.1016/j.prp.2022.154264
  10. Adv Biol Regul. 2022 Nov 29. pii: S2212-4926(22)00076-8. [Epub ahead of print] 100936
    Silencing effects of mutant RAS signalling on transcriptomes.
    Christine Sers, Reinhold Schäfer.
      Mutated genes of the RAS family encoding small GTP-binding proteins drive numerous cancers, including pancreatic, colon and lung tumors. Besides the numerous effects of mutant RAS gene expression on aberrant proliferation, transformed phenotypes, metabolism, and therapy resistance, the most striking consequences of chronic RAS activation are changes of the genetic program. By performing systematic gene expression studies in cellular models that allow comparisons of pre-neoplastic with RAS-transformed cells, we and others have estimated that 7 percent or more of all transcripts are altered in conjunction with the expression of the oncogene. In this context, the number of up-regulated transcripts approximates that of down-regulated transcripts. While up-regulated transcription factors such as MYC, FOSL1, and HMGA2 have been identified and characterized as RAS-responsive drivers of the altered transcriptome, the suppressed factors have been less well studied as potential regulators of the genetic program and transformed phenotype in the breadth of their occurrence. We therefore have collected information on downregulated RAS-responsive factors and discuss their potential role as tumor suppressors that are likely to antagonize active cancer drivers. To better understand the active mechanisms that entail anti-RAS function and those that lead to loss of tumor suppressor activity, we focus on the tumor suppressor HREV107 (alias PLAAT3 [Phospholipase A and acyltransferase 3], PLA2G16 [Phospholipase A2, group XVI] and HRASLS3 [HRAS-like suppressor 3]). Inactivating HREV107 mutations in tumors are extremely rare, hence epigenetic causes modulated by the RAS pathway are likely to lead to down-regulation and loss of function.
    Keywords:  Class II tumor suppressor genes; DNA methylation; HRASLS gene family; HREV107; N-acyltransferase; O-acyltransferase; PLA2G16; PLAAT3; Phospholipase 1/2
    DOI:  https://doi.org/10.1016/j.jbior.2022.100936
  11. J Med Chem. 2022 Dec 12.
    Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions.
    Jindi Huang, Liye Chen, Jiangxia Wu, Daiqiao Ai, Ji-Quan Zhang, Tie-Gen Chen, Ling Wang.
      The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01070
  12. Science. 2022 Dec 16. 378(6625): eabq5209
    Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function.
    Wonyul Jang, Dmytro Puchkov, Paula Samsó, YongTian Liang, Michal Nadler-Holly, Stephan J Sigrist, Ulrich Kintscher, Fan Liu, Kamel Mamchaoui, Vincent Mouly, Volker Haucke.
      Cells respond to fluctuating nutrient supply by adaptive changes in organelle dynamics and in metabolism. How such changes are orchestrated on a cell-wide scale is unknown. We show that endosomal signaling lipid turnover by MTM1, a phosphatidylinositol 3-phosphate [PI(3)P] 3-phosphatase mutated in X-linked centronuclear myopathy in humans, controls mitochondrial morphology and function by reshaping the endoplasmic reticulum (ER). Starvation-induced endosomal recruitment of MTM1 impairs PI(3)P-dependent contact formation between tubular ER membranes and early endosomes, resulting in the conversion of ER tubules into sheets, the inhibition of mitochondrial fission, and sustained oxidative metabolism. Our results unravel an important role for early endosomal lipid signaling in controlling ER shape and, thereby, mitochondrial form and function to enable cells to adapt to fluctuating nutrient environments.
    DOI:  https://doi.org/10.1126/science.abq5209
  13. FASEB J. 2023 Jan;37(1): e22707
    AKT1 phosphorylates RBM17 to promote Sox2 transcription by modulating alternative splicing of FOXM1 to enhance cancer stem cell properties in colorectal cancer cells.
    Yan Fu, Chen Bai, Shengsheng Wang, Denggang Chen, Peng Zhang, Hailang Wei, Fan Rong, Chao Zhang, Shaojuan Chen, Zhenjun Wang.
      Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The existence of cancer stem cells (CSC) causes tumor relapses, metastasis, and resistance to conventional therapy. Alternative splicing has been shown to affect physiological and pathological processes. Accumulating evidence has confirmed that targeting alternative splicing could be an effective strategy to treat CRC. Currently, the role of alternative splicing in the regulation of CSC properties in CRC has not been elucidated. Here, we show that RBM17 displays oncogenic roles in CRC cells. RBM17 enhances cell proliferation and reduces chemotherapeutic-induced apoptosis in CRC cells. Besides, RBM17 increases CD133 positive and ALDEFLUOR positive populations and promotes sphere formation in CRC cells. In mechanism studies, we found that FOXM1 is critical for RBM17 enhanced CSC properties. Moreover, FOXM1 alternative splicing is essential for RBM17 enhanced CSC properties in CRC cells. Additionally, RBM17 enhances CSC characteristics by controlling FOXM1 expression to promote Sox2 expression. Furthermore, AKT1 works as an upstream kinase to control RBM17-mediated FOXM1 alternative splicing and enhancement of CSC properties in CRC cells. Our study reveals that AKT1-RBM17-FOXM1-Sox2 axis could be a potential target for modulating alternative splicing to reduce CSC properties in CRC cells.
    Keywords:  RBM17; alternative splicing; cancer stem cells; colorectal cancer
    DOI:  https://doi.org/10.1096/fj.202201255R
  14. J Neurosci. 2022 Dec 16. pii: JN-RM-1354-22. [Epub ahead of print]
    mTORC2 inhibition improves morphological effects of PTEN loss, but does not correct synaptic dysfunction or prevent seizures.
    Erin R Cullen, Kamran Tariq, Amy N Shore, Bryan W Luikart, Matthew C Weston.
      Hyperactivation of PI3K/PTEN-mTOR signaling during neural development is associated with focal cortical dysplasia (FCD), autism, and epilepsy. mTOR can signal through two major hubs, mTORC1 and mTORC2, both of which are hyperactive following PTEN loss of function (LOF). Here, we tested the hypothesis that genetic inactivation of the mTORC2 complex via deletion of Rictor is sufficient to rescue morphological and electrophysiological abnormalities in the dentate gyrus caused by PTEN loss, as well as generalized seizures. An established, early postnatal mouse model of PTEN loss in male and female mice showed spontaneous seizures that were not prevented by mTORC2 inactivation. This lack of rescue occurred despite the normalization or amelioration of many morphological and electrophysiological phenotypes. However, increased excitatory connectivity proximal to dentate gyrus granule neuron somas was not normalized by mTORC2 inactivation. Further studies demonstrated that, although mTORC2 inactivation largely rescued the dendritic arbor overgrowth caused by PTEN LOF, it increased synaptic strength and caused additional impairments of presynaptic function. These results suggest that a constrained increase in excitatory connectivity and co-occurring synaptic dysfunction is sufficient to generate seizures downstream of PTEN LOF, even in the absence of characteristic changes in morphological properties.SIGNIFICANCE STATEMENT:Homozygous deletion of the Pten gene in neuronal subpopulations in the mouse serves as a valuable model of epilepsy caused by mTOR hyperactivation. To better understand the physiological mechanisms downstream of Pten loss that cause epilepsy, as well as the therapeutic potential of targeted gene therapies, we tested whether genetic inactivation of the mTORC2 complex could improve the cellular, synaptic, and in vivo effects of Pten loss in the dentate gyrus. We found that mTORC2 inhibition improved or rescued all morphological effects of Pten loss in the dentate gyrus, but synaptic changes and seizures persisted. These data suggest that synaptic dysfunction can drive epilepsy caused by hyperactivation of PI3K/PTEN-mTOR, and that future therapies should focus on this mechanistic link.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1354-22.2022
  15. Biochem Pharmacol. 2022 Dec 12. pii: S0006-2952(22)00475-0. [Epub ahead of print] 115380
    Upregulation of PIK3IP1 monitors the anti-cancer activity of PI3Kα inhibitors in gastric cancer cells.
    Xu-Bin Ma, Yang Wang, Ying-Jie Jia, Ya-Jie Liu, Ying-Qi Tian, Ying Liu, Gui-Qin Hou, Yi-Chao Xu, Hong-Min Liu.
      Gastric cancer remains one of the most malignant cancers in the world. The target-based drugs approved by FDA for gastric cancer treatment includes only three targets and benefit a small portion of gastric cancer patients. PIK3CA, a confirmed oncogene, mutates in 7-25% gastric cancer patients. PI3Kα inhibitor BYL719 has been approved for treating specific breast cancer. However, there is no comprehensive study about PI3Kα inhibitor in gastric cancer. In this study, we found pharmacological inhibition or knockdown of PI3Kα effectively inhibited the proliferation of partial gastric cancer cells. Then, we systematically explored the potential biomarkers for predicting or monitoring treatment response according to previous reports and found that basal expression of several receptor tyrosine kinases was related with the sensitivity of gastric cancer cells to BYL719. Next, RNA-seq technique was utilized and showed that BYL719 inhibited Myc targets V2 gene set in sensitive gastric cancer cells, and western blotting further verified that c-Myc was only inhibited in sensitive gastric cancer cells. More importantly, we firstly found BYL719 significantly elevated the expression of PIK3IP1 in sensitive gastric cancer cells, which was also observed in NCI-N87 cell derived xenograft mice models. Meanwhile, knockdown of PIK3IP1 partially rescued the cell growth inhibited by BYL719 in sensitive gastric cancer cells, suggesting the important role of PIK3IP1 in the antitumor activity of BYL719. In conclusion, our study provides biological evidence that PI3Kα is a promising target in specific gastric cancer and the elevation of PIK3IP1 could supply as a biomarker that monitoring treatment response.
    Keywords:  BYL719; Drug sensitivity; Gastric cancer; PI3Kα; PIK3IP1
    DOI:  https://doi.org/10.1016/j.bcp.2022.115380
  16. Cancers (Basel). 2022 Nov 22. pii: 5739. [Epub ahead of print]14(23):
    NDRG1 in Cancer: A Suppressor, Promoter, or Both?
    Vaibhavi Joshi, Sunil R Lakhani, Amy E McCart Reed.
      N-myc downregulated gene-1 (NDRG1) has been variably reported as a metastasis suppressor, a biomarker of poor outcome, and a facilitator of disease progression in a range of different cancers. NDRG1 is poorly understood in cancer due to its context-dependent and pleiotropic functions. Within breast cancer, NDRG1 is reported to be either a facilitator of, or an inhibitor of tumour progression and metastasis. The wide array of roles played by NDRG1 are dependent on post-translational modifications and subcellular localization, as well as the cellular context, for example, cancer type. We present an update on NDRG1, and its association with hallmarks of cancer such as hypoxia, its interaction with oncogenic proteins such as p53 as well its role in oncogenic and metastasis pathways in breast and other cancers. We further comment on its functional implications as a metastasis suppressor and promoter, its clinical relevance, and discuss its therapeutic targetability in different cancers.
    Keywords:  NDRG1; biomarker; metastasis; therapeutic target; tumour suppressor
    DOI:  https://doi.org/10.3390/cancers14235739
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