bims-pimaco 2024-08-18 papers

bims-pimaco

Biomed News

on PI3K and MAPK signalling in colorectal cancer

Issue of 2024–08–18
nine papers selected by
Lucas B. Zeiger

Post-Translational Modification of PTEN Protein: Quantity and Activity.
Functional and structural insights into RAS effector proteins.
Capturing RAS oligomerization on a membrane.
Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.
mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.
A Novel CRISPR/Cas9-mediated mouse model of colon carcinogenesis.
A systematic review of mechanisms of PTEN gene down-regulation mediated by miRNA in prostate cancer.
Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms.
Remodelling of the translatome controls diet and its impact on tumorigenesis.

Oncol Rev. 2024 ;18 1430237

Post-Translational Modification of PTEN Protein: Quantity and Activity.

Xiao Li, Pu Yang, Xiaoli Hou, Shaoping Ji.

  Post-translational modifications play crucial roles in regulating protein functions and stabilities. PTEN is a critical tumor suppressor involved in regulating cellular proliferation, survival, and migration processes. However, dysregulation of PTEN is common in various human cancers. PTEN stability and activation/suppression have been extensively studied in the context of tumorigenesis through inhibition of the PI3K/AKT signaling pathway. PTEN undergoes various post-translational modifications, primarily including phosphorylation, acetylation, ubiquitination, SUMOylation, neddylation, and oxidation, which finely tune its activity and stability. Generally, phosphorylation modulates PTEN activity through its lipid phosphatase function, leading to altered power of the signaling pathways. Acetylation influences PTEN protein stability and degradation rate. SUMOylation has been implicated in PTEN localization and interactions with other proteins, affecting its overall function. Neddylation, as a novel modification of PTEN, is a key regulatory mechanism in the loss of tumor suppressor function of PTEN. Although current therapeutic approaches focus primarily on inhibiting PI3 kinase, understanding the post-translational modifications of PTEN could help provide new therapeutic strategies that can restore PTEN's role in PIP3-dependent tumors. The present review summarizes the major recent developments in the regulation of PTEN protein level and activity. We expect that these insights will contribute to better understanding of this critical tumor suppressor and its potential implications for cancer therapy in the future.

Keywords:  PTEN; SUMOylation; acetylation; phosphorylation; ubiquitination

DOI:  https://doi.org/10.3389/or.2024.1430237
Mol Cell. 2024 Aug 13. pii: S1097-2765(24)00622-1. [Epub ahead of print]

Functional and structural insights into RAS effector proteins.

Alessandro M Mozzarelli, Dhirendra K Simanshu, Pau Castel.

DOI: https://doi.org/10.1016/j.molcel.2024.07.024
Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2405986121

Capturing RAS oligomerization on a membrane.

Sangho D Yun, Elena Scott, Jing-Yuan Chang, Hanieh Bahramimoghaddam, Michael Lynn, Carter Lantz, David H Russell, Arthur Laganowsky.

  RAS GTPases associate with the biological membrane where they function as molecular switches to regulate cell growth. Recent studies indicate that RAS proteins oligomerize on membranes, and disrupting these assemblies represents an alternative therapeutic strategy. However, conflicting reports on RAS assemblies, ranging in size from dimers to nanoclusters, have brought to the fore key questions regarding the stoichiometry and parameters that influence oligomerization. Here, we probe three isoforms of RAS [Kirsten Rat Sarcoma viral oncogene (KRAS), Harvey Rat Sarcoma viral oncogene (HRAS), and Neuroblastoma oncogene (NRAS)] directly from membranes using mass spectrometry. We show that KRAS on membranes in the inactive state (GDP-bound) is monomeric but forms dimers in the active state (GTP-bound). We demonstrate that the small molecule BI2852 can induce dimerization of KRAS, whereas the binding of effector proteins disrupts dimerization. We also show that RAS dimerization is dependent on lipid composition and reveal that oligomerization of NRAS is regulated by palmitoylation. By monitoring the intrinsic GTPase activity of RAS, we capture the emergence of a dimer containing either mixed nucleotides or GDP on membranes. We find that the interaction of RAS with the catalytic domain of Son of Sevenless (SOScat) is influenced by membrane composition. We also capture the activation and monomer to dimer conversion of KRAS by SOScat. These results not only reveal the stoichiometry of RAS assemblies on membranes but also uncover the impact of critical factors on oligomerization, encompassing regulation by nucleotides, lipids, and palmitoylation.

Keywords:  RAS; cancer; mass spectrometry; peripheral membrane protein

DOI:  https://doi.org/10.1073/pnas.2405986121
Mol Cancer. 2024 Aug 10. 23(1): 164

Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.

Hongyao Li, Xiang Wen, Yueting Ren, Zhichao Fan, Jin Zhang, Gu He, Leilei Fu.

  The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding to cell surface receptor stimulation, while class II and III are more involved in membrane transport. Under normal physiological conditions, the PI3K signaling network orchestrates cell growth, division, migration and survival. Aberrant activation of the PI3K signaling pathway disrupts cellular activity and metabolism, often marking the onset of cancer. Currently, the Food and Drug Administration (FDA) has approved the clinical use of five class I PI3K inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different class I PI3K family members, are primarily used in the treatment of breast cancer and hematologic malignancies. Therefore, the development of novel class I PI3K inhibitors has been a prominent research focus in the field of oncology, aiming to enhance potential therapeutic selectivity and effectiveness. In this review, we summarize the specific structures of PI3Ks and their functional roles in cancer progression. Additionally, we critically evaluate small molecule inhibitors that target class I PI3K, with a particular focus on their clinical applications in cancer treatment. Moreover, we aim to analyze therapeutic approaches for different types of cancers marked by aberrant PI3K activation and to identify potential molecular targets amenable to intervention with small-molecule inhibitors. Ultimately, we propose future directions for the development of therapeutic strategies that optimize cancer treatment outcomes by modulating the PI3K family.

Keywords:  Cancer therapy; Class I PI3K; Clinical applications; Molecular target; PI3K family; Small-molecule inhibitor; Therapeutic approach

DOI:  https://doi.org/10.1186/s12943-024-02072-1
Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2405959121

mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.

Stefania Battaglioni, Louise-Marie Craigie, Sofia Filippini, Timm Maier, Michael N Hall.

  TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.

Keywords:  LST2; TOS motif; mTOR signaling; negative feedback; phosphorylation substrate

DOI:  https://doi.org/10.1073/pnas.2405959121
Cell Mol Gastroenterol Hepatol. 2024 Aug 09. pii: S2352-345X(24)00145-0. [Epub ahead of print] 101390

A Novel CRISPR/Cas9-mediated mouse model of colon carcinogenesis.

Hajime Kashima, Anthony Fischer, Daniel A Veronese-Paniagua, Vered A Gazit, Changqing Ma, Yan Yan, Marc S Levin, Blair B Madison, Deborah C Rubin.

   BACKGROUND & AIMS: Human sporadic colorectal cancer (CRC) results from a multistep pathway with sequential acquisition of specific genetic mutations in the colorectal epithelium. Modeling CRC in vivo is critical for understanding the tumor microenvironment. To accurately recapitulate human CRC pathogenesis, mouse models must include these multi-step genetic abnormalities.
AIMS: Generate a sporadic CRC model that more closely mimics this multi-step process and use this model to study the role of a novel Let7 target PLAGL2 in CRC pathogenesis.
METHODS: We generated a CRISPR/Cas9 somatic mutagenesis mouse model that is inducible and multiplexed for simultaneous inactivation of multiple genes involved in CRC pathogenesis. We used both a doxycycline-inducible transcriptional activator and a dox-inactivated transcriptional repressor to achieve tight, non-leaky expression of the Cas9 nickase. This mouse has transgenic expression of multiple guide RNAs to induce sporadic inactivation in the gut epithelium of four tumor suppressor genes commonly mutated in CRC, Apc, Pten, Smad4 and Trp53. These were crossed to Vil-LCL-PLAGL2 mice which have Cre-inducible overexpression of PLAGL2 in the gut epithelium.
RESULTS: These mice exhibited random somatic mutations in all four targeted tumor suppressor genes, resulting in multiple adenomas and adenocarcinomas in the small bowel and colon. Crosses with Vil-LCL-PLAGL2 mice demonstrated that gut-specific PLAGL2 overexpression increased colon tumor growth.
CONCLUSIONS: This conditional model represents a new CRISPR/Cas9-mediated mouse model of colorectal carcinogenesis. These mice can be used to investigate the role of novel, previously uncharacterized genes in CRC, in the context of multiple commonly mutated tumor suppressor genes and thus more closely mimic human CRC pathogenesis.

Keywords:  CRISPR/Cas9; PLAGL2; colorectal neoplasia; mouse models

DOI:  https://doi.org/10.1016/j.jcmgh.2024.101390
Heliyon. 2024 Aug 15. 10(15): e34950

A systematic review of mechanisms of PTEN gene down-regulation mediated by miRNA in prostate cancer.

Fernando Bergez-Hernández, Martín Irigoyen-Arredondo, Alejandra Martínez-Camberos.

   Background: The Phosphatase and Tensin Homolog gene (PTEN) is pivotal in regulating diverse cellular processes, including growth, differentiation, proliferation, and cell survival, mainly by modulating the PI3K/AKT/mTOR pathway. Alterations in the expression of the PTEN gene have been associated with epigenetic mechanisms, particularly the regulation by small non-coding RNAs, such as miRNAs. Modifications in the expression levels of miRNAs that control PTEN have been shown to lead to its underexpression. This underexpression, in turn, impacts the PI3K/AKT/mTOR pathway, thereby influencing crucial mechanisms like proliferation and apoptosis, playing an important role in the initiation and progression of prostate cancer (PCa). Thus, we aimed to systematically reviewed available information concerning the regulation of PTEN mediated by miRNA in PCa.
Methods: Electronic databases were searched to identify studies assessing PTEN regulation via PCa miRNAs, the search included combination of the words microRNAs, PTEN and prostatic neoplasms. The quality assessment of the articles included was carried out using an adapted version of SYRCLE and CASP tool.
Results: We included 39 articles that measured the relative gene expression of miRNAs in PCa and their relationship with PTEN regulation. A total of 42 miRNAs were reported involved in the development and progression of PCa via PTEN dysregulation (34 miRNAs up-regulated and eight miRNAs down-regulated). Sixteen miRNAs were shown as the principal regulators for genetic interactions leading to carcinogenesis, being the miR-21 the most reported in PCa associated with PTEN down-regulation. We showed the silencing of PTEN could be promoted by a loop between miR-200b and DNMT1 or by direct targeting of PTEN by microRNAs, leading to the constitutive activation of PI3K/AKT/mTOR and interactions with intermediary genes support apoptosis inhibition, proliferation, invasion, and metastasis in PCa.
Conclusion: According to our review, dysregulation of PTEN mediated mainly by miR-21, -20a, -20b, -93, -106a, and -106b up-regulation has a central role in PCa development and could be potential biomarkers for diagnosis, prognostic, and therapeutic targets.

Keywords:  Epigenetic regulation; PTEN; Prostate cancer; miRNA

DOI:  https://doi.org/10.1016/j.heliyon.2024.e34950
Nat Cancer. 2024 Aug 15.

Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms.

Xiaojing Chu, Xiangjie Li, Yu Zhang, Guohui Dang, Yuhui Miao, Wenbin Xu, Jinyu Wang, Zemin Zhang, Sijin Cheng.

The tumor microenvironment (TME) considerably influences colorectal cancer (CRC) progression, therapeutic response and clinical outcome, but studies of interindividual heterogeneities of the TME in CRC are lacking. Here, by integrating human colorectal single-cell transcriptomic data from approximately 200 donors, we comprehensively characterized transcriptional remodeling in the TME compared to noncancer tissues and identified a rare tumor-specific subset of endothelial cells with T cell recruitment potential. The large sample size enabled us to stratify patients based on their TME heterogeneity, revealing divergent TME subtypes in which cancer cells exploit different immune evasion mechanisms. Additionally, by associating single-cell transcriptional profiling with risk genes identified by genome-wide association studies, we determined that stromal cells are major effector cell types in CRC genetic susceptibility. In summary, our results provide valuable insights into CRC pathogenesis and might help with the development of personalized immune therapies.

DOI: https://doi.org/10.1038/s43018-024-00807-z
Nature. 2024 Aug 14.

Remodelling of the translatome controls diet and its impact on tumorigenesis.

Haojun Yang, Vincenzo Andrea Zingaro, James Lincoff, Harrison Tom, Satoshi Oikawa, Juan A Oses-Prieto, Quinn Edmondson, Ian Seiple, Hardik Shah, Shingo Kajimura, Alma L Burlingame, Michael Grabe, Davide Ruggero.

Fasting is associated with a range of health benefits1-6. How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting7,8. We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting. We show that P-eIF4E is responsible for controlling the translation of genes involved in lipid catabolism and the production of ketone bodies. Inhibiting P-eIF4E impairs ketogenesis in response to fasting and a ketogenic diet. P-eIF4E regulates those messenger RNAs through a specific translation regulatory element within their 5' untranslated regions (5' UTRs). Our findings reveal a new signalling property of fatty acids, which are elevated during fasting. We found that fatty acids bind and induce AMP-activated protein kinase (AMPK) kinase activity that in turn enhances the phosphorylation of MAP kinase-interacting protein kinase (MNK), the kinase that phosphorylates eIF4E. The AMPK-MNK-eIF4E axis controls ketogenesis, revealing a new lipid-mediated kinase signalling pathway that links ketogenesis to translation control. Certain types of cancer use ketone bodies as an energy source9,10 that may rely on P-eIF4E. Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.

DOI: https://doi.org/10.1038/s41586-024-07781-7