bims-pimaco 2022-06-05 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2022–06–05
eight papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine.
Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer.
MUC3A promotes the progression of colorectal cancer through the PI3K/Akt/mTOR pathway.
Mutation of KRAS in colorectal adenocarcinoma in Greenland.
Non-canonical mTORC1 signaling at the lysosome.
TIFA promotes CRC cell proliferation via RSK- and PRAS40- dependent manner.
Colorectal Cancer: Advancing Science, Improving Access, and Refining Therapy.
Cannabinoid Receptor-1 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR.

J Biol Chem. 2022 May 27. pii: S0021-9258(22)00525-7. [Epub ahead of print] 102084

mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine.

Mahabub Alam, Hiroki Shima, Yoshitaka Matsuo, Chi Long Nguyen, Mitsuyo Matsumoto, Yusho Ishii, Nichika Sato, Takato Sugiyama, Risa Nobuta, Satoshi Hashimoto, Liang Liu, Mika K Kaneko, Yukinari Kato, Toshifumi Inada, Kazuhiko Igarashi.

  Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mTORC1 activity, but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A or availability of SAM. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient.

Keywords:  S-adenosylmethionine; mTORC1; methionine adenosyltransferase 2A; methylation; ribosome; translation; translation factor

DOI:  https://doi.org/10.1016/j.jbc.2022.102084
J Exp Clin Cancer Res. 2022 Jun 02. 41(1): 184

Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer.

Lu Yang, Arup Bhattacharya, Yun Li, Sandra Sexton, Xiang Ling, Fengzhi Li, Yuesheng Zhang.

   BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab, are valuable therapeutics for colorectal cancer (CRC), but resistance to these inhibitors is common. The reason for such resistance is not well understood, which hampers development of better therapeutic strategies. Although activating mutations in KRAS, BRAF and PIK3CA are considered major drivers of CRC resistance to EGFR inhibitors, therapeutic targeting of these drug resistance drivers has not produced substantial clinical benefit.
METHODS: We exploited cell lines and mouse tumor models (cell line xenografts and patient derived xenografts) for experiments of genetic and pharmacologic depletion of EGFR and/or its family member HER2, including EGFR mutants, inhibition of EGFR ligand shedding, and biochemical analysis of signaling proteins, to delineate the mechanism of CRC resistance to EGFR inhibitors and to assess the therapeutic activity of PEPDG278D, which is a recombinant human protein that induces the degradation of both EGFR and HER2.
RESULTS: The sensitivity of CRC cells to cetuximab and panitumumab correlates with the ability of these drugs to induce EGFR downregulation. PEPDG278D strongly inhibits oncogenic signaling and growth of CRC cells by causing profound depletion of EGFR and HER2, regardless of activating mutations of KRAS, BRAF and PIK3CA. siRNA knockdown of EGFR or HER2 also inhibits CRC cells resistant to EGFR inhibitors. Tumors harboring mutated KRAS, BRAF and/or PIK3CA also overexpress EGFR ligands, further suggesting that EGFR signaling remains important to the tumors. While excessive tumor-generated high-affinity EGFR ligands block target engagement by PEPDG278D, aderbasib, an inhibitor of ADAM10 and ADAM17, enables PEPDG278D to exert strong antitumor activity by inhibiting ligand shedding. Moreover, adding fluorouracil, which is commonly used in CRC treatment, to the combination of PEPDG278D and aderbasib further enhances tumor inhibition.
CONCLUSIONS: Our study shows that CRC resistance to EGFR inhibitors results primarily from the inability of the inhibitors to downregulate their target and that a PEPDG278D-based combination treatment overcomes the resistance.

Keywords:  Aderbasib; Cetuximab; Colorectal cancer; EGFR; HER2; PEPDG278D; Panitumumab; Therapeutic resistance

DOI:  https://doi.org/10.1186/s13046-022-02389-z
BMC Cancer. 2022 Jun 02. 22(1): 602

MUC3A promotes the progression of colorectal cancer through the PI3K/Akt/mTOR pathway.

Wei Su, Baijie Feng, Lina Hu, Xianzhi Guo, Minghua Yu.

  Mucin 3A (MUC3A) is overexpressed in colorectal cancer (CRC) and associated with poor prognosis, but the related mechanism remains unclear. Our study found that MUC3A promotes the progression of CRC by activating the PI3K/Akt/mTOR signaling pathway. Knockout of MUC3A significantly inhibited the proliferation of CRC cells and induced G1 phase arrest by upregulating p21 protein, an important cell cycle regulator. Moreover, knockout of MUC3A significantly inhibited invasion ability and enhanced the sensitivity to the chemotherapeutic agent 5-FU. Furthermore, we found that knockout of MUC3A repressed the PI3K/Akt/mTOR pathway through RNA-seq. Treatment with the PI3K/Akt/mTOR pathway inhibitor rapamycin successfully eliminated the difference in proliferation, invasion and chemoresistance between MUC3A knockout cells and control cells. Our study suggests that MUC3A is a potential oncogene that promotes the proliferation, invasion, and chemotherapy resistance of CRC. Moreover, CRC patients with high expression of MUC3A may benefit from rapamycin treatment.

Keywords:  Akt; Cancer progression; Cell cycle; Colorectal cancer; MUC3A; PI3K; mTOR pathway

DOI:  https://doi.org/10.1186/s12885-022-09709-8
APMIS. 2022 Jun 02.

Mutation of KRAS in colorectal adenocarcinoma in Greenland.

Nabi Mousavi, Sarah Line Bring Truelsen, Simon Bernth-Andersen, Anders Koch, Steffen Heegaard.

  KRAS mutation is one of the most frequent driver mutations in colorectal cancer (CRC) and is also a prognostic biomarker. The aim of the present study was to determine the frequency of KRAS mutations over time in the Greenlandic population diagnosed with CRC. In total, 578 patients with the diagnosis of adenocarcinoma between 1988 and 2017 were identified. The status of KRAS and the mutational subtypes of KRAS mutations were determined in 102 representative samples by the Idylla™ platform in the time periods 1988-1990, 2002-2004, and 2015-2017. The results showed that the frequency of the KRAS mutations increased significantly, from 27% in 1988-1990 to 43% in 2015-2017 (p < 0.001). Furthermore, the most frequent subtypes of KRAS mutations in Greenland were G12D (c.35G>A) with 14%, G12V (c.35G>T) with 7%, and G13D (c.38G>A) with 6%. In conclusion, this study showed that the frequency of KRAS mutations in CRC has been increasing in recent decades in the specific population of Greenland. The results of this study may be used in initiatives related to targeted therapy of CRC in specific ethnicities and in investigations focusing on the environmental factors of cancer-related somatic mutations.

Keywords:  Colorectal cancer; Greenland; Inuit; KRAS mutation; population genetics

DOI:  https://doi.org/10.1111/apm.13254
Trends Cell Biol. 2022 May 30. pii: S0962-8924(22)00117-9. [Epub ahead of print]

Non-canonical mTORC1 signaling at the lysosome.

Gennaro Napolitano, Chiara Di Malta, Andrea Ballabio.

  The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.

Keywords:  FLCN; Rag GTPases; TFEB; lysosome; mTORC1

DOI:  https://doi.org/10.1016/j.tcb.2022.04.012
Cancer Sci. 2022 May 30.

TIFA promotes CRC cell proliferation via RSK- and PRAS40- dependent manner.

Wenzhi Shen, Wenfei Du, Yanping Li, Yongming Huang, Xinyu Jiang, Chenglong Yang, Jiaping Tang, Huan Liu, Na Luo, Xiaoyuan Zhang, Zhixin Zhang.

  Previous studies have shown that TIFA (TNF receptor associated factor (TRAF)-interacting protein with a Forkhead-associated (FHA) domain) plays different roles in various tumor types. However, the function of TIFA in colorectal cancer (CRC) remains unclear. Here, we disclosed that the expression of TIFA was marked increased in CRC versus normal tissue, and positively correlated with CRC TNM stages. In agreement, we found that the CRC cell lines show increased TIFA expression levels versus normal control. The knockdown of TIFA inhibited cell proliferation but have no effects on cell apoptosis in vitro and in vivo. Moreover, the ectopic expression of TIFA enhanced cell proliferation ability in vitro and in vivo. In contrast, the expression of mutant TIFA (T9A, oligomerization site mutation; D6, TRAF6 binding site deletion) alternatively abolished TIFA mediated cell proliferation enhancement. Exploration of the underlying mechanism demonstrated that the protein synthesis associated kinase RSK and PRAS40 activation were all responsible for TIFA mediated CRC progression. In summary, the aforementioned findings suggest a model of TIFA in mediating CRC progression. This may provide a promising target for CRC therapy.

Keywords:  Colorectal Cancer; PRAS40; RSK; TIFA; cell proliferation

DOI:  https://doi.org/10.1111/cas.15432
Hematol Oncol Clin North Am. 2022 Jun;pii: S0889-8588(22)00034-X. [Epub ahead of print]36(3): xiii-xiv

Colorectal Cancer: Advancing Science, Improving Access, and Refining Therapy.

Benjamin L Schlechter, Kimmie Ng.

DOI: https://doi.org/10.1016/j.hoc.2022.04.001
Cell Death Discov. 2022 May 31. 8(1): 273

Cannabinoid Receptor-1 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR.

You-Ming Deng, Cheng Zhao, Lei Wu, Zhan Qu, Xin-Yu Wang.

Cannabinoid receptors, CB1 and CB2, have been implicated as emerging targets for cancer therapy. Herein, we investigated the potential regulation mechanism of CB1 and its implications in colorectal cancer. CB1 and EGFR expression were examined in colorectal cancer cell lines. The effects of CB1 agonist ACEA and its antagonist AM251 on the proliferation, migration and invasion of colorectal cancer cells and the expression of M1 and M2 macrophage markers were examined. EGFR overexpression was performed with plasmids containing EGFR gene. Tumor xenografts were constructed to explore the effects of CB1 activation on tumorigenesis. We showed that CB1 was downregulated while EGFR was upregulated in colorectal cancer cells. The activation of CB1 suppressed the proliferation, migration and invasion of colorectal cancer cells and the differentiation of M2 macrophages, while CB1 inhibition had opposite effects. Moreover, the alterations in tumorigenesis and M2 macrophage activation induced by CB1 activation were counteracted by EGFR overexpression. Besides, CB1 silencing promoted tumor cell proliferation and M2 polarization which was counteracted by EGFR knockdown. In vivo, CB1 activation also repressed tumorigenesis and M2 macrophage activation. The present study demonstrated that CB1 activation suppressed M2 macrophage through EGFR downregulation in colorectal cancers. These findings first unveiled the potential avenue of CB1 as a targeted therapy for colorectal cancer.

DOI: https://doi.org/10.1038/s41420-022-01064-8