bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2020‒11‒01
thirteen papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research


  1. Cell Death Dis. 2020 Oct 29. 11(10): 930
    Khawaja H, Campbell A, Roberts JZ, Javadi A, O'Reilly P, McArt D, Allen WL, Majkut J, Rehm M, Bardelli A, Di Nicolantonio F, Scott CJ, Kennedy R, Vitale N, Harrison T, Sansom OJ, Longley DB, Evergren E, Van Schaeybroeck S.
      RAS mutant (MT) metastatic colorectal cancer (mCRC) is resistant to MEK1/2 inhibition and remains a difficult-to-treat group. Therefore, there is an unmet need for novel treatment options for RASMT mCRC. RALA and RALB GTPases function downstream of RAS and have been found to be key regulators of several cell functions implicated in KRAS-driven tumorigenesis. However, their role as regulators of the apoptotic machinery remains to be elucidated. Here, we found that inhibition of RALB expression, but not RALA, resulted in Caspase-8-dependent cell death in KRASMT CRC cells, which was not further increased following MEK1/2 inhibition. Proteomic analysis and mechanistic studies revealed that RALB depletion induced a marked upregulation of the pro-apoptotic cell surface TRAIL Death Receptor 5 (DR5) (also known as TRAIL-R2), primarily through modulating DR5 protein lysosomal degradation. Moreover, DR5 knockdown or knockout attenuated siRALB-induced apoptosis, confirming the role of the extrinsic apoptotic pathway as a regulator of siRALB-induced cell death. Importantly, TRAIL treatment resulted in the association of RALB with the death-inducing signalling complex (DISC) and targeting RALB using pharmacologic inhibition or RNAi approaches triggered a potent increase in TRAIL-induced cell death in KRASMT CRC cells. Significantly, high RALB mRNA levels were found in the poor prognostic Colorectal Cancer Intrinsic Subtypes (CRIS)-B CRC subgroup. Collectively, this study provides to our knowledge the first evidence for a role for RALB in apoptotic priming and suggests that RALB inhibition may be a promising strategy to improve response to TRAIL treatment in poor prognostic RASMT CRIS-B CRC.
    DOI:  https://doi.org/10.1038/s41419-020-03131-3
  2. EBioMedicine. 2020 Oct 21. pii: S2352-3964(20)30444-8. [Epub ahead of print]61 103068
    Wei M, Ma Y, Shen L, Xu Y, Liu L, Bu X, Guo Z, Qin H, Li Z, Wang Z, Wu K, Yao L, Li J, Zhang J.
      BACKGROUND: Paracellular barriers play an important role in the pathogenesis of Inflammatory bowel disease (IBD) and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumour suppressor gene and to inhibit colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear.METHODS: Intestine-specific Ndrg2 deficiency mice (Ndrg2ΔIEC) were subjected to DSS- or TNBS-induced colitis, and AOM-DSS-induced colitis-associated tumour. HT29 cells, Caco2 cells, primary intestinal epithelial cells (IECs) from Ndrg2ΔIEC mice, mouse embryo fibroblasts (MEFs) from systemic Ndrg2 knockout mice, HEK293 cells and human UC and DC specimens were used to investigate NDRG2 function in colitis and colitis-associated tumour.
    FINDINGS: Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhanced the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation.
    INTERPRETATION: These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays an important role in gut homeostasis maintenance and colitis-associated tumour development.
    FUNDING: National Natural Science Foundation of China (No. 81770523, 31571437, 81672751), Creative Research Groups of China (No. 81421003), State Key Laboratory of Cancer Biology Project (CBSKL2019ZZ11, CBSKL201406, CBSKL2017Z08 and CBSKL2017Z11), Fund for Distinguished Young Scholars of ShaanXi province (2019JC-22).
    Keywords:  Adherens junction; Colitis; Colitis-associated colorectal cancer; NDRG2
    DOI:  https://doi.org/10.1016/j.ebiom.2020.103068
  3. Cancer Sci. 2020 Oct 30.
    Morishita K, Nakahata S, Ichikawa T.
      N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including adult T-cell leukemia/lymphoma (ATLL). NDRG2, as a stress-responsive protein, is induced by several stress-related signaling pathways and NDRG2 negatively regulates various signal transduction pathways. Although it has not been found to function alone, NDRG2 binds serine/threonine protein phosphatase 2A (PP2A), generating a complex that is involved in the regulation of various target proteins. The main function of NDRG2 is to maintain cell homeostasis by suppressing stress-induced signal transduction; however, in cancer, genomic deletions and/or promoter methylation may inhibit the expression of NDRG2, resulting in enhanced tumor development via overactivated signal transduction pathways. A wide variety of tumors develop in Ndrg2-deficient mice, including T-cell lymphoma, liver, lung and other tumors, the characteristics of which are similar to those in Pten-deficient mice. In particular, PTEN is a target molecule of the NDRG2/PP2A complex, which enhances PTEN phosphatase activity by dephosphorylating residues in the PTEN C-terminal region. In ATLL cells, loss of NDRG2 expression leads to the failed recruitment of PP2A to PTEN, resulting in the inactivation of PTEN phosphatase with phosphorylation, ultimately leading to the activation of PI3K/AKT. Thus, NDRG2, as a PP2A adaptor, regulates the global phosphorylation of important signaling molecules. Moreover, the downregulation of NDRG2 expression via long-term stress-induced methylation is directly correlated with the development of ATLL and other cancers. Thus, NDRG2 might be important for the development of stress-induced leukemia and other cancers and has become an important target for novel molecular therapies.
    Keywords:  ATLL; HSP90; NDRG2; PP2A; PTEN
    DOI:  https://doi.org/10.1111/cas.14716
  4. Nat Commun. 2020 Oct 30. 11(1): 5488
    Lee KM, Guerrero-Zotano AL, Servetto A, Sudhan DR, Lin CC, Formisano L, Jansen VM, González-Ericsson P, Sanders ME, Stricker TP, Raj G, Dean KM, Fiolka R, Cantley LC, Hanker AB, Arteaga CL.
      The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.
    DOI:  https://doi.org/10.1038/s41467-020-19291-x
  5. Cell Death Dis. 2020 Oct 26. 11(10): 919
    Gao W, Zhang Y, Luo H, Niu M, Zheng X, Hu W, Cui J, Xue X, Bo Y, Dai F, Lu Y, Yang D, Guo Y, Guo H, Li H, Zhang Y, Yang T, Li L, Zhang L, Hou R, Wen S, An C, Ma T, Jin L, Xu W, Wu Y.
      Spindle and kinetochore-associated complex subunit 3 (SKA3) is a well-known regulator of chromosome separation and cell division, which plays an important role in cell proliferation. However, the mechanism of SKA3 regulating tumor proliferation via reprogramming metabolism is unknown. Here, SKA3 is identified as an oncogene in laryngeal squamous cell carcinoma (LSCC), and high levels of SKA3 are closely associated with malignant progression and poor prognosis. In vitro and in vivo experiments demonstrate that SKA3 promotes LSCC cell proliferation and chemoresistance through a novel role of reprogramming glycolytic metabolism. Further studies reveal the downstream mechanisms of SKA3, which can bind and stabilize polo-like kinase 1 (PLK1) protein via suppressing ubiquitin-mediated degradation. The accumulation of PLK1 activates AKT and thus upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, resulting in enhancement of glycolysis. Furthermore, our data reveal that phosphorylation at Thr360 of SKA3 is critical for its binding to PLK1 and the increase in glycolysis. Collectively, the novel oncogenic signal axis "SKA3-PLK1-AKT" plays a critical role in the glycolysis of LSCC. SKA3 may serve as a prognostic biomarker and therapeutic target, providing a potential strategy for proliferation inhibition and chemosensitization in tumors, especially for LSCC patients with PLK1 inhibitor resistance.
    DOI:  https://doi.org/10.1038/s41419-020-03104-6
  6. Cancer Res. 2020 Oct 26. pii: canres.3923.2019. [Epub ahead of print]
    Restall IJ, Cseh O, Richards LM, Pugh TJ, Luchman HA, Weiss S.
      Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSC) has not yet been elucidated. Here we report that, across a panel of 19 glioblastoma BTSC lines, inhibition of glutaminase (GLS) showed a variable response from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered cells susceptible to GLS inhibition, triggering the AADR and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs and support the therapeutic targeting of upstream activators and downstream effectors of the AADR pathway in GBM. Moreover, they demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3923
  7. Nat Commun. 2020 10 29. 11(1): 5463
    Tripathi R, Liu Z, Jain A, Lyon A, Meeks C, Richards D, Liu J, He D, Wang C, Nespi M, Rymar A, Wang P, Wilson M, Plattner R.
      Metastatic melanoma remains an incurable disease for many patients due to the limited success of targeted and immunotherapies. BRAF and MEK inhibitors reduce metastatic burden for patients with melanomas harboring BRAF mutations; however, most eventually relapse due to acquired resistance. Here, we demonstrate that ABL1/2 kinase activities and/or expression are potentiated in cell lines and patient samples following resistance, and ABL1/2 drive BRAF and BRAF/MEK inhibitor resistance by inducing reactivation of MEK/ERK/MYC signaling. Silencing/inhibiting ABL1/2 blocks pathway reactivation, and resensitizes resistant cells to BRAF/MEK inhibitors, whereas expression of constitutively active ABL1/2 is sufficient to promote resistance. Significantly, nilotinib (2nd generation ABL1/2 inhibitor) reverses resistance, in vivo, causing prolonged regression of resistant tumors, and also, prevents BRAFi/MEKi resistance from developing in the first place. These data indicate that repurposing the FDA-approved leukemia drug, nilotinib, may be effective for prolonging survival for patients harboring BRAF-mutant melanomas.
    DOI:  https://doi.org/10.1038/s41467-020-19075-3
  8. Nat Commun. 2020 10 28. 11(1): 5439
    Hamarsheh S, Groß O, Brummer T, Zeiser R.
      Oncogenic KRAS mutations are the most frequent mutations in human cancer, but most difficult to target. While sustained proliferation caused by oncogenic KRAS-downstream signalling is a main driver of carcinogenesis, there is increasing evidence that it also mediates autocrine effects and crosstalk with the tumour microenvironment (TME). Here, we discuss recent reports connecting KRAS mutations with tumour-promoting inflammation and immune modulation caused by KRAS that leads to immune escape in the TME. We discuss the preclinical work on KRAS-induced inflammation and immune modulation in the context of currently ongoing clinical trials targeting cancer entities that carry KRAS mutations and strategies to overcome the oncogene-induced effects on the immune system.
    DOI:  https://doi.org/10.1038/s41467-020-19288-6
  9. Cells. 2020 Oct 27. pii: E2361. [Epub ahead of print]9(11):
    Slimane SN, Marcel V, Fenouil T, Catez F, Saurin JC, Bouvet P, Diaz JJ, Mertani HC.
      Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.
    Keywords:  cancer; colorectal; human; rDNA; rRNA; ribosome; targeting; translation
    DOI:  https://doi.org/10.3390/cells9112361
  10. Cells. 2020 Oct 22. pii: E2342. [Epub ahead of print]9(11):
    Turnham DJ, Bullock N, Dass MS, Staffurth JN, Pearson HB.
      Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K-AKT-mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K-AKT-mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.
    Keywords:  PI3K; PTEN; prostate cancer; targeted therapy
    DOI:  https://doi.org/10.3390/cells9112342
  11. Cell Death Differ. 2020 Oct 27.
    Cho JH, Kim K, Kim SA, Park S, Park BO, Kim JH, Kim SY, Kwon MJ, Han MH, Lee SB, Park BC, Park SG, Kim JH, Kim S.
      The mammalian Target of Rapamycin (mTOR) pathway regulates a variety of physiological processes, including cell growth and cancer progression. The regulatory mechanisms of these signals are extremely complex and comprise many feedback loops. Here, we identified the deubiquitinating enzyme ovarian tumor domain-containing protein 5 (OTUD5) as a novel positive regulator of the mTOR complex (mTORC) 1 and 2 signaling pathways. We demonstrated that OTUD5 stabilized β-transducin repeat-containing protein 1 (βTrCP1) proteins via its deubiquitinase (DUB) activity, leading to the degradation of Disheveled, Egl-10, and pleckstrin domain-containing mTOR-interacting protein (DEPTOR), which is an inhibitory protein of mTORC1 and 2. We also showed that mTOR directly phosphorylated OTUD5 and activated its DUB activity. RNA sequencing analysis revealed that OTUD5 regulates the downstream gene expression of mTOR. Additionally, OTUD5 depletion elicited several mTOR-related phenotypes such as decreased cell size and increased autophagy in mammalian cells as well as the suppression of a dRheb-induced curled wing phenotype by RNA interference of Duba, a fly ortholog of OTUD5, in Drosophila melanogaster. Furthermore, OTUD5 knockdown inhibited the proliferation of the cancer cell lines with mutations activating mTOR pathway. Our results suggested a positive feedback loop between OTUD5 and mTOR signaling pathway.
    DOI:  https://doi.org/10.1038/s41418-020-00649-z
  12. Mol Cell. 2020 Oct 21. pii: S1097-2765(20)30691-2. [Epub ahead of print]
    Li F, Kozono D, Deraska P, Branigan T, Dunn C, Zheng XF, Parmar K, Nguyen H, DeCaprio J, Shapiro GI, Chowdhury D, D'Andrea AD.
      While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A/PABIR1 confers cellular resistance to CHK1 inhibitors (CHK1is) and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1is. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1i plus a WEE1 inhibitor can overcome CHK1i resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1i sensitivity or resistance.
    Keywords:  CHK1 inhibitor; CRISPR sgRNA screening; FAM122A; Fanconi Anemia; PABIR1; PP2A; WEE1
    DOI:  https://doi.org/10.1016/j.molcel.2020.10.008
  13. iScience. 2020 Oct 23. 23(10): 101638
    Knatko EV, Tatham MH, Zhang Y, Castro C, Higgins M, Dayalan Naidu S, Leonardi C, de la Vega L, Honda T, Griffin JL, Hay RT, Dinkova-Kostova AT.
      Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH-associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism, allowing adaptation and survival under conditions of oxidative, inflammatory, and metabolic stress. Nrf2 is the principal determinant of redox homeostasis, and contributes to mitochondrial function and integrity and cellular bioenergetics. Using proteomics and lipidomics, we show that genetic downregulation of Keap1 in mice, and the consequent Nrf2 activation to pharmacologically relevant levels, leads to upregulation of carboxylesterase 1 (Ces1) and acyl-CoA oxidase 2 (Acox2), decreases triglyceride levels, and alters the lipidome. This is accompanied by downregulation of hepatic ATP-citrate lyase (Acly) and decreased levels of acetyl-CoA, a trigger for autophagy. These findings suggest that downregulation of Keap1 confers features of a fasted metabolic state, which is an important consideration in the drug development of Keap1-targeting pharmacologic Nrf2 activators.
    Keywords:  Human Metabolism; Molecular Biology; Omics
    DOI:  https://doi.org/10.1016/j.isci.2020.101638