The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy.
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ABSTRACT:
SUBMITTER: Michel M
PROVIDER: S-EPMC8150459 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies.
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Project description:Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.
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Project description:Oxaliplatin resistance is a major issue in the treatment of p53 mutant colorectal cancer (CRC). Finding the specific biomarkers would improve therapeutic efficacy of patients with CRC. In order to figure out the biomarker for CRC patients with mutant p53 access oxaliplatin, a Gene Expression Omnibus dataset (GSE42387) was used to determine differentially expressed genes (DEGs). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software were used to predict protein-protein interactions. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to group the DEGs into their common pathways. 138 DEGs were identified with 46 upregulated and 92 downregulated. In the PPI networks, 7 of the upregulated genes and 13 of the downregulated genes were identified as hub genes (high degrees). Four hub genes, aldehyde dehydrogenase 2 family member (ALDH2), aldo-keto reductase family 1 member B1 (AKR1B1), aldo-keto reductase family 1 member B10 (AKR1B10), and monoglyceride lipase (MGLL) were enriched in the most significant pathway, glycerolipid metabolism. Further, we found that low expression of ALDH2 is correlated with poor overall survival and oxaliplatin resistance. Finally, we found that combined treatment with ALDH2 inhibitor and oxaliplatin will reduce the sensitivity to oxaliplatin in p53 mutant HT29 cells. In conclusion, we demonstrate that ALDH2 may be a biomarker for oxaliplatin resistance status in CRC patients and bring new insight into treatment strategy for p53 mutant CRC patients.
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Project description:The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.
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Project description:Aberrant alternative splicing events play a critical role in cancer biology, contributing to tumor invasion, metastasis, epithelial-mesenchymal transition, and drug resistance. Recent studies have shown that alternative splicing is a key feature for transcriptomic variations in colorectal cancer, which ranks third among malignant tumors worldwide in both incidence and mortality. Long non-coding RNAs can modulate this process by acting as trans-regulatory agents, recruiting splicing factors, or driving them to specific targeted genes. LncH19 is a lncRNA dis-regulated in several tumor types and, in colorectal cancer, it plays a critical role in tumor onset, progression, and metastasis. In this paper, we found, that in colorectal cancer cells, the long non-coding RNA H19 can bind immature RNAs and splicing factors as hnRNPM and RBFOX2. Through bioinformatic analysis, we identified 57 transcripts associated with lncH19 and containing binding sites for both splicing factors, hnRNPM, and RBFOX2. Among these transcripts, we identified the mRNA of the GTPase-RAC1, whose alternatively spliced isoform, RAC1B, has been ascribed several roles in the malignant transformation. We confirmed, in vitro, the binding of the splicing factors to both the transcripts RAC1 and lncH19. Loss and gain of expression experiments in two colorectal cancer cell lines (SW620 and HCT116) demonstrated that lncH19 is required for RAC1B expression and, through RAC1B, it induces c-Myc and Cyclin-D increase. In vivo, investigation from biopsies of colorectal cancer patients showed higher levels of all the explored genes (lncH19, RAC1B, c-Myc and Cyclin-D) concerning the healthy counterpart, thus supporting our in vitro model. In addition, we identified a positive correlation between lncH19 and RAC1B in colorectal cancer patients. Finally, we demonstrated that lncH19, as a shuttle, drives the splicing factors RBFOX2 and hnRNPM to RAC1 allowing exon retention and RAC1B expression. The data shown in this paper represent the first evidence of a new mechanism of action by which lncH19 carries out its functions as an oncogene by prompting colorectal cancer through the modulation of alternative splicing.
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Project description:Inactivation of p53 functions is an almost universal feature of human cancer cells. This has spurred a tremendous effort to develop p53 based cancer therapies. Gene therapy using wild-type p53, delivered by adenovirus vectors, is now in widespread use in China. Other biologic approaches include the development of oncolytic viruses designed to replicate and kill only p53 defective cells and also the development of siRNA and antisense RNA's that activate p53 by inhibiting the function of the negative regulators Mdm2, MdmX, and HPV E6. The altered processing of p53 that occurs in tumor cells can elicit T-cell and B-cell responses to p53 that could be effective in eliminating cancer cells and p53 based vaccines are now in clinical trial. A number of small molecules that directly or indirectly activate the p53 response have also reached the clinic, of which the most advanced are the p53 mdm2 interaction inhibitors. Increased understanding of the p53 response is also allowing the development of powerful drug combinations that may increase the selectivity and safety of chemotherapy, by selective protection of normal cells and tissues.
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