bims-pimaco 2023-07-30 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–07–30
sixteen papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Alkaline intracellular pH (pHi) increases PI3K kinase activity to promote mTORC1 and mTORC2 signaling and function during growth factor limitation.
mTOR inhibition reprograms cellular proteostasis by regulating eIF3D-mediated selective mRNA translation and promotes cell phenotype switching.
CBF-beta mitigates PI3K-alpha-specific inhibitor killing through PIM1 in PIK3CA mutant gastric cancer.
Cooperative Genomic Lesions in HRAS-Mutant Cancers Predict Resistance to Farnesyltransferase Inhibitors.
2'-Deoxy Guanosine Nucleotides Alter the Biochemical Properties of Ras.
Bimodality in Ras signaling originates from processivity of the Ras activator SOS without classic kinetic bistability.
KRAS p.G12C Mutation in Metastatic Colorectal Cancer: Prognostic Implications and Advancements in Targeted Therapies.
Targeting RAF Isoforms and Tumor Microenvironments in RAS or BRAF Mutant Colorectal Cancers with SJ-C1044 for Anti-Tumor Activity.
Transcriptional Profiling and Consensus Molecular Subtype Assignment to Understand Response and Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Colorectal Cancer.
Potent and selective eradication of tumor cells by an EpCAM-targeted Ras-degrading enzyme.
Fluctuations of formin binding in the generation of membrane patterns.
ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway.
PI3K signaling-regulated metabolic reprogramming: From mechanism to application.
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK).
Evolutionarily divergent mTOR remodels translatome for tissue regeneration.
Role of the ER-induced UPR pathway, apoptosis, and autophagy in colorectal cancer.

J Biol Chem. 2023 Jul 26. pii: S0021-9258(23)02125-7. [Epub ahead of print] 105097

Alkaline intracellular pH (pHi) increases PI3K kinase activity to promote mTORC1 and mTORC2 signaling and function during growth factor limitation.

Dubek Kazyken, Stephen I Lentz, Maxwell Wadley, Diane C Fingar.

  The conserved protein kinase mTOR (mechanistic target of rapamycin) responds to diverse environmental cues to control cell metabolism and promote cell growth, proliferation, and survival as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTORC2. Our prior work demonstrated that an alkaline intracellular pH (pHi) increases mTORC2 activity and cell survival in complete media in part by activating AMPK, a kinase best known to sense energetic stress. It is important to note that an alkaline pHi represents an under-appreciated hallmark of cancer cells that promotes their oncogenic behaviors. In addition, mechanisms that control mTORC1 and mTORC2 signaling and function remain incompletely defined, particularly in response to stress conditions. Here, we demonstrate that an alkaline pHi increases PI3K activity to promote mTORC1 and mTORC2 signaling in the absence of serum growth factors. Alkaline pHi increases mTORC1 activity through PI3K-Akt signaling, which mediates inhibitory phosphorylation of the upstream proteins TSC2 and PRAS40 and dissociates TSC2 from lysosomal membranes, thus enabling Rheb-mediated activation of mTORC1. Thus, we show that an alkaline pHi mimics growth factor-PI3K signaling. Functionally, we also demonstrate that an alkaline pHi increases cap-dependent protein synthesis through inhibitory phosphorylation of 4EBP1 and suppresses apoptosis in a PI3K- and mTOR-dependent manner. We speculate that an alkaline pHi promotes a low, basal level of cell metabolism (e.g., protein synthesis) that enables cancer cells within growing tumors to proliferate and survive despite limiting growth factors and nutrients, in part through elevated PI3K-mTORC1 and/or PI3K-mTORC2 signaling.

Keywords:  Akt PKB; S6 kinase; apoptosis; cell signaling; eukaryotic translation initiation factor 4E (eIF4E); eukaryotic translation initiation factor 4E-binding protein (eIF4EBP1); pH regulation; phosphatidylinositide 3-kinase (PI 3-kinase); protein synthesis; target of rapamycin (TOR)

DOI:  https://doi.org/10.1016/j.jbc.2023.105097
Cell Rep. 2023 Jul 25. pii: S2211-1247(23)00879-3. [Epub ahead of print]42(8): 112868

mTOR inhibition reprograms cellular proteostasis by regulating eIF3D-mediated selective mRNA translation and promotes cell phenotype switching.

Sejeong Shin, Min-Joon Han, Mark P Jedrychowski, Ziyang Zhang, Kevan M Shokat, David R Plas, Noah Dephoure, Sang-Oh Yoon.

  Cells maintain and dynamically change their proteomes according to the environment and their needs. Mechanistic target of rapamycin (mTOR) is a key regulator of proteostasis, homeostasis of the proteome. Thus, dysregulation of mTOR leads to changes in proteostasis and the consequent progression of diseases, including cancer. Based on the physiological and clinical importance of mTOR signaling, we investigated mTOR feedback signaling, proteostasis, and cell fate. Here, we reveal that mTOR targeting inhibits eIF4E-mediated cap-dependent translation, but feedback signaling activates a translation initiation factor, eukaryotic translation initiation factor 3D (eIF3D), to sustain alternative non-canonical translation mechanisms. Importantly, eIF3D-mediated protein synthesis enables cell phenotype switching from proliferative to more migratory. eIF3D cooperates with mRNA-binding proteins such as heterogeneous nuclear ribonucleoprotein F (hnRNPF), heterogeneous nuclear ribonucleoprotein K (hnRNPK), and Sjogren syndrome antigen B (SSB) to support selective mRNA translation following mTOR inhibition, which upregulates and activates proteins involved in insulin receptor (INSR)/insulin-like growth factor 1 receptor (IGF1R)/insulin receptor substrate (IRS) and interleukin 6 signal transducer (IL-6ST)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. Our study highlights the mechanisms by which cells establish the dynamic change of proteostasis and the resulting phenotype switch.

Keywords:  CP: Cell biology; CP: Molecular biology; eIF3D; eIF4E; mRNA translation; mTOR; proteome; proteostasis

DOI:  https://doi.org/10.1016/j.celrep.2023.112868
Mol Cancer Res. 2023 Jul 26. pii: MCR-23-0034. [Epub ahead of print]

CBF-beta mitigates PI3K-alpha-specific inhibitor killing through PIM1 in PIK3CA mutant gastric cancer.

Lyla J Stanland, Hazel X Ang, Jacob P Hoj, Yunqiang Chu, Patrick Tan, Kris C Wood, Micah A Luftig.

PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4-25% of gastric cancers display activating PIK3CA mutations including 80% of EBV-associated GCs. Small molecules including pan-PI3K and dual PI3K/mTOR inhibitors have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study we identified modulators of the response to the PI3K-alpha-specific inhibitor, BYL719, in PIK3CA mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hyper-sensitivity to BYL719, through increased cell cycle arrest and cell death, respectively. Additionally, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to up-regulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3K-alpha inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3K-alpha inhibitor response in PIK3CA mutant gastric tumors and can inform future work as mutant selective inhibitors are in development for diverse tumor types. Implications: Loss of either NEDD9 or BCL-XL confers hyper-sensitivity to PI3K-alpha inhibition while loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0034
Res Sq. 2023 Jul 14. pii: rs.3.rs-3154719. [Epub ahead of print]

Cooperative Genomic Lesions in HRAS-Mutant Cancers Predict Resistance to Farnesyltransferase Inhibitors.

Aradhya Nigam, Gnana Krishnamoorthy, Walid Chatila, Katherine Berman, Mahesh Saqcena, Henry Walch, Alan Ho, Nikolaus Schultz, James Fagin, Brian Untch.

The clinical development of farnesyltransferase inhibitors (FTI) for HRAS -mutant tumors showed mixed responses dependent on cancer type. Co-occurring mutations may affect response. We aimed to uncover cooperative genetic events specific to HRAS -mutant tumors and study their effect on FTI sensitivity. Using targeted sequencing data from MSK-IMPACT and DFCI-GENIE databases we identified co-mutations in HRAS - vs KRAS - and NRAS -mutant cancers. HRAS -mutant cancers had a higher frequency of co-altered mutations (48.8%) in MAPK, PI3K, or RTK pathways genes compared to KRAS - and NRAS -mutant cancers (41.4% and 38.4%, respectively; p < 0.05). Class 3 BRAF , NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS -mutant lineages. To study the effect of comutations on FTI sensitivity, Hras G13R was transfected into 'RASless' ( Kras lox/lox ; Hras -/- ; Nras -/- ) mouse embryonic fibroblasts (MEFs) which sensitized non-transfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion or Pik3ca H1047R or Braf G466E transduction led to relative resistance to tipifarnib in Hras G13R MEFs in the presence or absence of Kras WT . Combined treatment of tipifarnib with MEK inhibition sensitized cells to tipifarnib, including in MEFs with PI3K pathway comutations. HRAS -mutant tumors demonstrate lineage demonstrate lineage-dependent MAPK/PI3K pathway alterations that confer relative resistance to tipifarnib. Combined FTI and MEK inhibition is a promising combination for HRAS -mutant tumors.

DOI: https://doi.org/10.21203/rs.3.rs-3154719/v1
Biochemistry. 2023 Jul 24.

2'-Deoxy Guanosine Nucleotides Alter the Biochemical Properties of Ras.

Sangho D Yun, Elena Scott, Zahra Moghadamchargari, Arthur Laganowsky.

Ras proteins in the mitogen-activated protein kinase (MAPK) signaling pathway represent one of the most frequently mutated oncogenes in cancer. Ras binds guanosine nucleotides and cycles between active (GTP) and inactive (GDP) conformations to regulate the MAPK signaling pathway. Guanosine and other nucleotides exist in cells as either 2'-hydroxy or 2'-deoxy forms, and imbalances in the deoxyribonucleotide triphosphate pool have been associated with different diseases, such as diabetes, obesity, and cancer. However, the biochemical properties of Ras bound to dGNP are not well understood. Herein, we use native mass spectrometry to monitor the intrinsic GTPase activity of H-Ras and N-Ras oncogenic mutants, revealing that the rate of 2'-deoxy guanosine triphosphate (dGTP) hydrolysis differs compared to the hydroxylated form, in some cases by seven-fold. Moreover, K-Ras expressed from HEK293 cells exhibited a higher than anticipated abundance of dGNP, despite the low abundance of dGNP in cells. Additionally, the GTPase and dGTPase activity of K-RasG12C was found to be accelerated by 10.2- and 3.8-fold in the presence of small molecule covalent inhibitors, which may open opportunities for the development of Pan-Ras inhibitors. The molecular assemblies formed between H-Ras and N-Ras, including mutant forms, with the catalytic domain of SOS (SOScat) were also investigated. The results show that the different mutants of H-Ras and N-Ras not only engage SOScat differently, but these assemblies are also dependent on the form of guanosine triphosphate bound to Ras. These findings bring to the forefront a new perspective on the nucleotide-dependent biochemical properties of Ras that may have implications for the activation of the MAPK signaling pathway and Ras-driven cancers.

DOI: https://doi.org/10.1021/acs.biochem.3c00258
bioRxiv. 2023 Jul 17. pii: 2023.07.17.549263. [Epub ahead of print]

Bimodality in Ras signaling originates from processivity of the Ras activator SOS without classic kinetic bistability.

Albert A Lee, Neil H Kim, Steven Alvarez, He Ren, Joseph B DeGrandchamp, L J Nugent Lew, Jay T Groves.

Ras is a small GTPase that is central to important functional decisions in diverse cell types. An important aspect of Ras signaling is its ability to exhibit bimodal, or switch-like activity. We describe the total reconstitution of a receptor-mediated Ras activation-deactivation reaction catalyzed by SOS and p120-RasGAP on supported lipid membrane microarrays. The results reveal a bimodal Ras activation response, which is not a result of classic kinetic bistability, but is rather driven by the distinct processivity of the Ras activator, SOS. Furthermore, the bimodal response is controlled by the condensation state of the scaffold protein, LAT, to which SOS is recruited. Processivity-driven bimodality leads to stochastic bursts of Ras activation even under strongly deactivating conditions. This behavior contrasts classic kinetic bistability and is distinctly more resistant to pharmacological inhibition.

DOI: https://doi.org/10.1101/2023.07.17.549263
Cancers (Basel). 2023 Jul 12. pii: 3579. [Epub ahead of print]15(14):

KRAS p.G12C Mutation in Metastatic Colorectal Cancer: Prognostic Implications and Advancements in Targeted Therapies.

Alessandro Ottaiano, Francesco Sabbatino, Francesco Perri, Marco Cascella, Roberto Sirica, Renato Patrone, Maurizio Capuozzo, Giovanni Savarese, Monica Ianniello, Nadia Petrillo, Luisa Circelli, Vincenza Granata, Massimiliano Berretta, Mariachiara Santorsola, Guglielmo Nasti.

  KRAS is frequently mutated in tumors. It is mutated in approximately 30% of all cancer cases and in nearly 50% of cases of metastatic colorectal cancer (CRC), which is the third leading cause of cancer-related deaths worldwide. Recent advancements in understanding CRC biology and genetics have highlighted the significance of KRAS mutations in the progression of CRC. The KRAS gene encodes a small GTPase (Guanosine TriPhosphatases) that plays a key role in signaling pathways associated with important proteins involved in amplifying growth factor and receptor signals. Mutations in KRAS are frequently observed in codons 12 and 13, and these mutations have oncogenic properties. Abnormal activation of KRAS proteins strongly stimulates signals associated with various cancer-related processes in CRC, including cell proliferation, migration and neoangiogenesis. In this review, we explore the distinct prognostic implications of KRAS mutations. Specifically, the KRAS p.G12C mutation is associated with a worse prognosis in metastatic CRC. The correlation between structure, conformation and mutations is visually presented to emphasize how alterations in individual amino acids at the same position in a single protein can unexpectedly exhibit complex involvement in cancer. Last, KRAS p.G12C is discussed as an emerging and promising therapeutic target in metastatic CRC, providing a concise overview of available clinical data regarding the use of new inhibitors.

Keywords:  KRAS; genetics; metastatic colorectal cancer; p.G12C mutation; prognosis

DOI:  https://doi.org/10.3390/cancers15143579
Curr Issues Mol Biol. 2023 Jul 13. 45(7): 5865-5878

Targeting RAF Isoforms and Tumor Microenvironments in RAS or BRAF Mutant Colorectal Cancers with SJ-C1044 for Anti-Tumor Activity.

Sungpyo Hong, Myeongjin Jeon, Jeonghee Kwon, Hanbyeol Park, Goeun Lee, Kilwon Kim, Soonkil Ahn.

  Colorectal cancer (CRC) is a significant global health issue characterized by a high prevalence of KRAS gene mutations. The RAS/MAPK pathway, involving KRAS, plays a crucial role in CRC progression. Although some RAS inhibitors have been approved, their efficacy in CRC is limited. To overcome these limitations, pan-RAF inhibitors targeting A-Raf, B-Raf, and C-Raf have emerged as promising therapeutic strategies. However, resistance to RAF inhibition and the presence of an immunosuppressive tumor microenvironment (TME) pose additional obstacles to effective therapy. Here, we evaluated the potential of a novel pan-RAF inhibitor, SJ-C1044, for targeting mutant KRAS-mediated signaling and inhibiting CRC cell proliferation. Notably, SJ-C1044 also exhibited inhibitory effects on immunokinases, specifically, CSF1R, VEGFR2, and TIE2, which play crucial roles in immune suppression. SJ-C1044 demonstrated potent antitumor activity in xenograft models of CRC harboring KRAS or BRAF mutations. Importantly, treatment with SJ-C1044 resulted in increased infiltration of T cells and reduced presence of tumor-associated macrophages and regulatory T cells within the TME. Thus, SJ-C1044 shows immunomodulatory potential and the ability to enhance antitumor responses. The study underscores the therapeutic potential of SJ-C1044 as a novel pan-RAF inhibitor capable of targeting oncogenic signaling pathways and overcoming immune suppression in CRC.

Keywords:  CSF1R; KRAS; colorectal cancer; pan-RAF; tumor-associated macrophages

DOI:  https://doi.org/10.3390/cimb45070371
JCO Precis Oncol. 2023 Jul;7 e2200422

Transcriptional Profiling and Consensus Molecular Subtype Assignment to Understand Response and Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Colorectal Cancer.

Saikat Chowdhury, Ria Gupta, Joshua Millstein, Kangyu Lin, Valsala Haridas, Mohammad A Zeineddine, Christine Parseghian, Heinz-Josef Lenz, Scott Kopetz, John Paul Shen.

PURPOSE: Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti-epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with RASWT tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy.
MATERIALS AND METHODS: Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes.
RESULTS: Restricting to RASWT patients, we observed that CMS2 tumors (canonical subtype) had significantly higher response rates relative to other CMS when treated with cetuximab combination with doublet chemotherapy (Okita et al cohort: 92% disease control rate (DCR) for CMS2, chi-square P = .04; CALGB/SWOG 80405 cohort: 90% objective response rate (ORR) for CMS2, chi-square P < .001) and with single-agent cetuximab (68%, chi-square P = .01). CMS2 tumors showed best response among right-sided (ORR = 80%) and left-sided (ORR = 92%) tumors in the CALGB/SWOG 80405 cohort. CMS2 cells lines were most likely to be sensitive to cetuximab (60%) and CMS2 patient-derived xenograft had the highest DCR (84%). We found Myc, E2F, and mammalian target of rapamycin pathways were consistently upregulated in resistant samples (enrichment score >1, false discovery rate <0.25). Inhibitors of these pathways in resistant cell lines exhibited additive effects with cetuximab.
CONCLUSION: These data suggest that CRC transcriptional profiles, when used to assign CMS, provide additional ability to predict response to anti-EGFR therapy relative to using tumor sidedness alone. Notably both right-sided and left-sided CMS2 tumors had excellent response, suggesting that anti-EGFR therapy be included as a treatment option for right-sided CMS2 tumors.

DOI: https://doi.org/10.1200/PO.22.00422
Mol Ther Oncolytics. 2023 Sep 21. 30 16-26

Potent and selective eradication of tumor cells by an EpCAM-targeted Ras-degrading enzyme.

Valentina Palacio-Castañeda, Bas van de Crommert, Elke Verploegen, Mike Overeem, Jenny van Oostrum, Wouter P R Verdurmen.

  Despite decades of efforts, an urgent need remains to develop tumor cell-selective rat sarcoma (Ras)-targeting therapies that can treat patients with Ras-driven tumors. Here we report modular engineered proteins that degrade Ras selectively in tumor cells that overexpress the tumor cell marker epithelial cell adhesion molecule (EpCAM) by fusing the Ras degrader Ras-Rap1-specific endopeptidase with the translocation domain of the Pseudomonas aeruginosa exotoxin A (ETA) or diphtheria toxin (DT). Redirection to EpCAM is achieved by a designed ankyrin repeat protein. In two-dimensional tumor cell cultures, complete degradation of Ras proteins after 24 h was observed with EpCAM-targeted Ras degraders fused to ETA or DT in EpCAM-overexpressing MCF7 and HCT116 cells, with median inhibition concentration values at sub-nanomolar levels. The viability of EpCAM-low non-cancerous fibroblasts remained unaffected. In a three-dimensional (3D) tumor-on-a-chip system that mimics the natural tumor microenvironment, effective Ras degradation and selective toxicity toward tumor cells, particularly with the ETA-fused constructs, was determined on-chip. To conclude, we demonstrate the potential of modular engineered proteins to kill tumor cells highly selectively by simultaneously exploiting EpCAM as a tumor-specific cell surface molecule as well as Ras as an intracellular oncotarget in a 3D system mimicking the natural tumor microenvironment.

Keywords:  Pseudomonas aeruginosa exotoxin A; Ras-Rap1-specific endopeptidase; designed ankyrin repeat protein; diphtheria toxin; epithelial cell adhesion molecule; tumor-specific targeting

DOI:  https://doi.org/10.1016/j.omto.2023.06.002
Biophys J. 2023 Jul 24. pii: S0006-3495(23)00465-4. [Epub ahead of print]

Fluctuations of formin binding in the generation of membrane patterns.

Mary Ecke, Jana Prassler, Günther Gerisch.

  Circular actin waves that propagate on the substrate-attached membrane of Dictyostelium cells separate two distinct membrane domains from each other: an inner territory rich in phosphatidyl-(3,4,5) trisphosphate (PIP3), and an external area decorated with the PIP3-degrading 3-phosphatase PTEN. During wave propagation, the inner territory increases on the expense of the external area. Beyond a size limit, the inner territory becomes unstable, breaking into an inner and an external domain. The sharp boundary between these domains is demarcated by the insertion of an actin wave. During the conversion of inner territory to external area, the state of the membrane fluctuates, as visualized by dynamic landscapes of Formin B binding. Here we analyze the Formin B fluctuations in relation to three markers of the membrane state: activated Ras, PIP3, and PTEN.

Keywords:  PTEN; Ras; actin waves; formin; phosphatidylinositides

DOI:  https://doi.org/10.1016/j.bpj.2023.07.014
J Cancer. 2023 ;14(11): 1946-1955

ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway.

Shengnan Sun, Yong Yi, Zhi-Xiong Jim Xiao, Hu Chen.

  Colorectal cancer (CRC) is the fourth most diagnosed cancer worldwide. 43% of CRCs harbor p53 mutations. The tumor suppressor p53 induces cell growth arrest and/or apoptosis in response to stress, including endoplasmic reticulum (ER) stress. It has been documented that the p53 gene is mutated in more than 50% of human tumors and loses its tumor suppressor function, suggesting that ER stress-induced apoptosis might not rely on p53. In this study, we found that activation of ER stress promotes p53 null colon cancer cell apoptosis concomitant with an increased level of the TAp73α protein, a homologue of p53 in vitro and in vivo. Knockdown of TAp73α partially restores ER stress-induced apoptosis, indicating that ER stress stimulates apoptosis in a manner dependent on TAp73α, but not p53. Furthermore, we found that ER stress activates TAp73α mRNA and protein expression through PERK signalling, a branch of the unfolded protein response (UPR). Moreover, PERK promotes TAp73α expression by upregulating the expression of the transcription factor ATF4. ATF4 directly activates the transcription of TAp73α. Consistent with this finding, ATF4 knockdown inhibited PERK- or ER stress-induced TAp73α expression. Our findings reveal that ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 signalling. Therefore, prolonged ER stress or upregulation of TAp73α might be a therapeutic strategy for colon cancer.

Keywords:  ATF4; Cell apoptosis; ER stress; PERK; TAp73α

DOI:  https://doi.org/10.7150/jca.84170
Biochim Biophys Acta Rev Cancer. 2023 Jul 24. pii: S0304-419X(23)00101-4. [Epub ahead of print] 188952

PI3K signaling-regulated metabolic reprogramming: From mechanism to application.

Wen Ya Su, Lu Yao Tian, Lan Pin Guo, Lu Qi Huang, Wen Yuan Gao.

  Oncogenic signaling involved in tumor metabolic reprogramming. Tumorigenesis was not only determined by the mutations or deletion of oncogenes but also accompanied by the reprogramming of cellular metabolism. Metabolic alterations play a crucial regulatory role in the development and progression of tumors. Oncogenic PI3K/AKT signaling mediates the metabolic switch in cancer cells and immune cells in the tumor microenvironment. PI3K/AKT and its downstream effector branch off and connect to multiple steps of metabolism, such as glucose, lipids, and amino acids. Thus, PI3K inhibitor could effectively regulate metabolic pathway and impede the oncogenic process and some key metabolic proteins or critical enzymes also constitute biomarkers for tumor diagnosis and treatment. In the current review, we summarize the significant effect of PI3K/AKT signaling toward tumor metabolism, it enables us to obtain the better understanding for this interaction and develop more effective therapeutic strategies targeting cancer cell metabolism.

Keywords:  Amino acid metabolism; Fatty acid metabolism; Glycolysis; Metabolic reprogramming; PI3K/AKT

DOI:  https://doi.org/10.1016/j.bbcan.2023.188952
J Enzyme Inhib Med Chem. 2023 Dec;38(1): 2237209

Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK).

Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca.

  Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

Keywords:  AKT; PI3K; PIKK; anticancer therapy; inhibitors

DOI:  https://doi.org/10.1080/14756366.2023.2237209
Nature. 2023 Jul 26.

Evolutionarily divergent mTOR remodels translatome for tissue regeneration.

Olena Zhulyn, Hannah D Rosenblatt, Leila Shokat, Shizhong Dai, Duygu Kuzuoglu-Öztürk, Zijian Zhang, Davide Ruggero, Kevan M Shokat, Maria Barna.

An outstanding mystery in biology is why some species, such as the axolotl, can regenerate tissues whereas mammals cannot1. Here, we demonstrate that rapid activation of protein synthesis is a unique feature of the injury response critical for limb regeneration in the axolotl (Ambystoma mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components that are selectively activated at the level of translation from pre-existing messenger RNAs in response to injury. By contrast, protein synthesis is not activated in response to non-regenerative digit amputation in the mouse. We identify the mTORC1 pathway as a key upstream signal that mediates tissue regeneration and translational control in the axolotl. We discover unique expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR (axmTOR) in human cells, we show that these changes create a hypersensitive kinase that allows axolotls to maintain this pathway in a highly labile state primed for rapid activation. This change renders axolotl mTOR more sensitive to nutrient sensing, and inhibition of amino acid transport is sufficient to inhibit tissue regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in a highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.

DOI: https://doi.org/10.1038/s41586-023-06365-1
Pathol Res Pract. 2023 Jul 21. pii: S0344-0338(23)00406-5. [Epub ahead of print]248 154706

Role of the ER-induced UPR pathway, apoptosis, and autophagy in colorectal cancer.

Elmira Aboutalebi Vand Beilankouhi, Mir Amirhossein Sajadi, Iraj Alipourfard, Peyman Hassani, Mohammad Valilo, Reza Safaralizadeh.

  When large amounts of misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER) in response to stress, a process called unfolded protein response (UPR) is activated. The disruption of this process leads to many diseases including diabetes, neurodegenerative diseases, and many cancers. In the process of UPR in response to stress and unfolded proteins, specific signaling pathways are induced in the endoplasmic reticulum and subsequently transmitted to the nucleus and cytoplasm, causing homeostasis and restoring the cell's normal condition with reducing protein translation and synthesis. The UPR response followed by stress enhancement balances cell survival with death, therefore in this condition cells decide either to survive or have the path of apoptosis ahead. However, in some cases, this balance is disturbed and the UPR pathway is chronically activated or not activated and the cell conditions lead to cancer. This study aimed to briefly investigate the association between ER stress, UPR, apoptosis, and autophagy in colorectal cancer (CRC). Moreover, in current study, we will try to demonstrate canonical ways and methods for the treatment of CRC cells with attenuated ER stress.

Keywords:  Apoptosis; Chaperone; Colorectal cancer; ER stress; Unfolded protein response

DOI:  https://doi.org/10.1016/j.prp.2023.154706