bims-pimaco 2024-09-01 papers

bims-pimaco

Biomed News

on PI3K and MAPK signalling in colorectal cancer

Issue of 2024–09–01
seven papers selected by
Lucas B. Zeiger

Potentiation by Protein Synthesis Inducers of Translational Readthrough of Pathogenic Premature Termination Codons in PTEN Isoforms.
PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes.
NHEJ is promoted by the phosphorylation and phosphatase activity of PTEN via regulation of DNA-PKcs.
Unveiling the Role of PIK3R1 in Cancer: A Comprehensive Review of Regulatory Signaling and Therapeutic Implications.
LAT1 expression in colorectal cancer cells is unresponsive to HIF-1/2α accumulation under experimental hypoxia.
From lab to clinic: The discovery and optimization journey of PI3K inhibitors.
Lactate Oxidase Disrupts Lactate-Activated RAS and PI3K Oncogenic Signaling.

Cancers (Basel). 2024 Aug 13. pii: 2836. [Epub ahead of print]16(16):

Potentiation by Protein Synthesis Inducers of Translational Readthrough of Pathogenic Premature Termination Codons in PTEN Isoforms.

Leire Torices, Caroline E Nunes-Xavier, Rafael Pulido.

  The PTEN tumor suppressor is frequently targeted in tumors and patients with PTEN hamartoma tumor syndrome (PHTS) through nonsense mutations generating premature termination codons (PTC) that may cause the translation of truncated non-functional PTEN proteins. We have previously described a global analysis of the readthrough reconstitution of the protein translation and function of the human canonical PTEN isoform by aminoglycosides. Here, we report the efficient functional readthrough reconstitution of the PTEN translational isoform PTEN-L, which displays a minimal number of PTC in its specific N-terminal extension in association with disease. We illustrate the importance of the specific PTC and its nucleotide proximal sequence for optimal readthrough and show that the more frequent human PTEN PTC variants and their mouse PTEN PTC equivalents display similar patterns of readthrough efficiency. The heterogeneous readthrough response of the different PTEN PTC variants was independent of the length of the PTEN protein being reconstituted, and we found a correlation between the amount of PTEN protein being synthesized and the PTEN readthrough efficiency. Furthermore, combination of aminoglycosides and protein synthesis inducers increased the readthrough response of specific PTEN PTC. Our results provide insights with which to improve the functional reconstitution of human-disease-related PTC pathogenic variants from PTEN isoforms by increasing protein synthesis coupled to translational readthrough.

Keywords:  PHTS; genetic disease; precision therapy; premature termination codon; translational readthrough

DOI:  https://doi.org/10.3390/cancers16162836
Cancer Genomics Proteomics. 2024 Sep-Oct;21(5):21(5): 533-548

PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes.

Ioannis A Voutsadakis.

   BACKGROUND/AIM: Despite therapeutic advancements, metastatic colorectal cancer is usually fatal, necessitating novel approaches based on the molecular pathogenesis to improve outcomes. Some colorectal cancers have no mutations in the extended RAS panel (KRAS, NRAS, BRAF) genes and represent a special subset, which deserves particular therapeutic considerations.
MATERIALS AND METHODS: The genomic landscape of colorectal cancers from publicly available genomic series was interrogated, using the cBioportal platform. Colorectal cancer cohorts with cancers devoid of KRAS/NRAS or BRAF mutations were evaluated for the presence of mutations in the catalytic sub-unit alpha of kinase PI3K, encoded by the gene PIK3CA.
RESULTS: PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations were observed in 3.7% to 7.6% of colorectal cancers in the different series examined. Patients with all four genes in wildtype configuration (quadruple wild type) represented 32.2% to 39.9% of cases in the different series examined. Compared with quadruple wild type cancers, triple (KRAS/NRAS/BRAF) wild type/PIK3CA mutated cancers had a higher prevalence of high TMB cases and additional mutations in colorectal cancer associated genes except for mutations in TP53. Mutations in genes encoding for epigenetic modifiers and the DNA damage response (DDR) were also more frequent in triple wild type/PIK3CA mutated cancers. The prognosis of the two groups was comparable.
CONCLUSION: Colorectal cancers with PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations have frequently mutations in epigenetic modifiers and DDR response genes, which may provide opportunities for targeting. These mutations are present in a smaller subset of quadruple wild type cancers.

Keywords:  PI3K; extended RAS panel; genomic studies; quadruple wild type; targeted therapy

DOI:  https://doi.org/10.21873/cgp.20470
Biochim Biophys Acta Mol Cell Res. 2024 Aug 27. pii: S0167-4889(24)00171-X. [Epub ahead of print]1871(8): 119828

NHEJ is promoted by the phosphorylation and phosphatase activity of PTEN via regulation of DNA-PKcs.

Sougata Ghosh Chowdhury, Sandip Misra, Ginia Ghosh, Ananda Mukherjee, Priyanka Gopi, Prateek Pandya, Md Maidul Islam, Parimal Karmakar.

  DNA double-strand breaks (DSBs) are considered one of the most harmful forms of DNA damage. These DSBs are repaired through non-homologous end joining (NHEJ) and homologous recombination (HR) pathways and defects in these processes can lead to genomic instability and promote tumorigenesis. Phosphatase and Tensin homolog (PTEN) are crucial in HR repair. However, its involvement in the NHEJ repair pathway has remained elusive. In this study, we investigate the function of epigenetic regulation of PTEN in the NHEJ repair pathway. Our findings indicate that both the phosphorylation and phosphatase activity of PTEN are required for efficient NHEJ-mediated DSB repair. During the DNA damage response, we observed a reduced expression and chromatin attachment of the key NHEJ proteins, including Ku70/80, DNA-PKcs, XRCC4, and XLF, in PTEN-null cells. This reduction was attributed to the instability of these NHEJ proteins, as confirmed by our protein half-life assay. We have demonstrated that the DNA-PKcs inhibitor, NU7026, suppresses the DNA damage-induced phosphorylation of the C-terminal of PTEN. Thus, our study indicates that PTEN could be a target of DNA-PKcs. Protein-protein docking analysis also shows that PTEN interacts with the C-terminal region of DNA-PKcs. PTEN null cells exhibit compromised DNA-PKcs foci after DNA damage as it is in a hyper-phosphorylated state. Phospho-PTEN assists in recruiting DNA-PKcs on the DNA damage site by maintaining its hypo-phosphorylated state which also depends on its phosphatase activity. Therefore, after DNA damage, crosstalk between PTEN and DNA-PKcs modulates the NHEJ pathway. Thus, during DNA damage, PTEN gets phosphorylated directly or indirectly by DNA-PKcs and attaches to chromatin, resulting in the dephosphorylation of DNA-PKcs and subsequently recruitment of other NHEJ factors on chromatin occurs for efficient execution of the NHEJ pathway. Thus, our research provides a molecular understanding of the epigenetic regulation of PTEN and its significant role in controlling the NHEJ pathway.

Keywords:  DNA-PKcs; NHEJ; PTEN; Post-translational modulation

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119828
Semin Cancer Biol. 2024 Aug 26. pii: S1044-579X(24)00062-2. [Epub ahead of print]

Unveiling the Role of PIK3R1 in Cancer: A Comprehensive Review of Regulatory Signaling and Therapeutic Implications.

Ishita Gupta, Daria A Gaykalova.

  Phosphoinositide 3-kinase (PI3K) is responsible for phosphorylating phosphoinositides to generate secondary signaling molecules crucial for regulating various cellular processes, including cell growth, survival, and metabolism. The PI3K is a heterodimeric enzyme complex comprising of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85). The binding of the regulatory subunit, p85, with the catalytic subunit, p110, forms an integral component of the PI3K enzyme. PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) belongs to class IA of the PI3K family. PIK3R1 exhibits structural complexity due to alternative splicing, giving rise to distinct isoforms, prominently p85α and p55α. While the primary p85α isoform comprises multiple domains, including Src homology 3 (SH3) domains, a Breakpoint Cluster Region Homology (BH) domain, and Src homology 2 (SH2) domains (iSH2 and nSH2), the shorter isoform, p55α, lacks certain domains present in p85α. In this review, we will highlight the intricate regulatory mechanisms governing PI3K signaling along with the impact of PIK3R1 alterations on cellular processes. We will further delve into the clinical significance of PIK3R1 mutations in various cancer types and their implications for prognosis and treatment outcomes. Additionally, we will discuss the evolving landscape of targeted therapies aimed at modulating PI3K-associated pathways. Overall, this review will provide insights into the dynamic interplay of PIK3R1 in cancer, fostering advancements in precision medicine and the development of targeted interventions.

Keywords:  PI3K; PIK3R1; cancer; p85α; therapeutic targets; tumor suppressor

DOI:  https://doi.org/10.1016/j.semcancer.2024.08.004
Sci Rep. 2024 08 23. 14(1): 19635

LAT1 expression in colorectal cancer cells is unresponsive to HIF-1/2α accumulation under experimental hypoxia.

Ryuichi Ohgaki, Yuma Hirase, Minhui Xu, Hiroki Okanishi, Yoshikatsu Kanai.

  L-type amino acid transporter 1 (LAT1) is upregulated in various cancer types and contributes to disease progression. Previous studies have demonstrated or suggested that hypoxia-inducible factors (HIFs), the key transcription factors in hypoxic responses, control the expression of LAT1 gene in several types of cancer cells. However, this regulatory relationship has not been investigated yet in colorectal cancer (CRC), one of the cancer types in which the increased LAT1 expression holds prognostic significance. In this study, we found that neither LAT1 mRNA nor protein is induced under hypoxic condition (1% O2) in CRC HT-29 cells in vitro, regardless of the prominent HIF-1/2α accumulation and HIFs-dependent upregulation of glucose transporter 1. The hypoxic treatment generally did not increase either the mRNA or protein expression of LAT1 in eight CRC cell lines tested, in contrast to the pronounced upregulation by amino acid restriction. Interestingly, knockdown of von Hippel-Lindau ubiquitin ligase to inhibit the proteasomal degradation of HIFs caused an accumulation of HIF-2α and increased the LAT1 expression in certain CRC cell lines. This study contributes to delineating the molecular mechanisms responsible for the pathological expression of LAT1 in CRC cells, emphasizing the ambiguity of HIFs-dependent transcriptional upregulation of LAT1 across cancer cells.

Keywords:  Amino acid transporter; Colorectal cancer; Hypoxia; Hypoxia-inducible factor; LAT1; Transcriptional regulation

DOI:  https://doi.org/10.1038/s41598-024-70603-3
Eur J Med Chem. 2024 Aug 20. pii: S0223-5234(24)00667-6. [Epub ahead of print]277 116786

From lab to clinic: The discovery and optimization journey of PI3K inhibitors.

Siyu Lian, Zhenhua Du, Qingqing Chen, Yu Xia, Xinxin Miao, Weiwei Yu, Qian Sun, Chong Feng.

  PI3K inhibitors have emerged as promising therapeutic agents due to their critical role in various cellular processes, particularly in cancer, where the PI3K pathway is frequently dysregulated. This review explores the evolutionary path of PI3K inhibitors from laboratory discovery to clinical application. The journey begins with early laboratory investigations into PI3K signaling and inhibitor development, highlighting fundamental discoveries that laid the foundation for subsequent advancements. Optimization strategies, including medicinal chemistry approaches and structural modifications, are scrutinized for their contributions to enhancing inhibitor potency, selectivity, and pharmacokinetic properties. The translation from preclinical studies to clinical trials is examined, emphasizing pivotal trials that evaluated efficacy and safety profiles. Challenges encountered during clinical development are critically assessed. Finally, the review discusses ongoing research directions and prospects for PI3K inhibitors, underscoring these agents' continuous evolution and therapeutic potential.

Keywords:  Cancer therapy; Clinical trials; Content; Drug development; PI3K pathway; Targeted therapy

DOI:  https://doi.org/10.1016/j.ejmech.2024.116786
Cancers (Basel). 2024 Aug 10. pii: 2817. [Epub ahead of print]16(16):

Lactate Oxidase Disrupts Lactate-Activated RAS and PI3K Oncogenic Signaling.

Chandler R Keller, Steve R Martinez, Alexys Keltz, Michelle Chen, Weimin Li.

  LOX was recently shown to inhibit cancer cell proliferation and tumor growth. The mechanism of this inhibition, however, has been exclusively attributed to LOX depletion of TME lactate, a cancer cell energy source, and production of H2O2, an oxidative stressor. We report that TME lactate triggers the assembly of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1)-associated protein complex, which includes GRB2, SOS1, KRAS, GAB1, and PI3K, for the activation of both the RAS and the PI3K oncogenic signaling pathways in breast cancer (BCa) cells. LOX treatment decreased the levels of the proteins in the protein complex via induction of their proteasomal degradation. In addition, LOX inhibited lactate-stimulated expression of the lactate transporters MCT1 and MCT4. Our data suggest that HCAR1 activation by lactate is crucial for the assembly and function of the RAS and PI3K signaling nexus. Shutting down lactate signaling by disrupting this nexus could be detrimental to cancer cells. HCAR1 is therefore a promising target for the control of the RAS and the PI3K signaling required for BCa progression. Thus, our study provides insights into lactate signaling regulation of cancer progression and extends our understanding of LOX's functional mechanisms that are fundamental for exploring its therapeutic potential.

Keywords:  RAS/PI3K signaling; breast cancer (BCa); lactate oxidase (LOX); lactate receptor HCAR1; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers16162817