Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited.
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ABSTRACT:
SUBMITTER: Hall DCN
PROVIDER: S-EPMC9250486 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aspirin is one of the most promising over-the-counter drugs to repurpose for cancer treatment. In particular, aspirin has been reported to be effective against PIK3CA-mutated colorectal cancer (CRC); however, little information is available on how the PIK3CA gene status affects its efficacy. We found that the growth inhibitory effects of aspirin were impaired upon glutamine deprivation in PIK3CA-mutated CRC cells. Notably, glutamine dependency of aspirin-mediated growth inhibition was observed in PIK3CA-mutated cells but not PIK3CA wild type cells. Mechanistically, aspirin induced G1 arrest in PIK3CA-mutated CRC cells and inhibited the mTOR pathway, inducing the same phenotypes as glutamine deprivation. Moreover, our study including bioinformatic approaches revealed that aspirin increased the expression levels of glutaminolysis-related genes with upregulation of activating transcription factor 4 (ATF4) in PIK3CA-mutated CRC cells. Lastly, the agents targeting glutaminolysis demonstrated significant combined effects with aspirin on PIK3CA-mutated CRC cells. Thus, these findings not only suggest the correlation among aspirin efficacy, PIK3CA mutation and glutamine metabolism, but also the rational combinatorial treatments of aspirin with glutaminolysis-targeting agents against PIK3CA-mutated CRC.
| S-EPMC7281071 | biostudies-literature
Project description:BackgroundRegular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers.MethodsWe obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1.ResultsAmong patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer-specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction).ConclusionsRegular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.).
| S-EPMC3532946 | biostudies-literature
Project description:The impact of aspirin use after the diagnosis of colorectal cancer is unknown. Among others, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutational status was proposed as a molecular biomarker for the response to adjuvant aspirin therapy. However, prognostic data on aspirin use after a colorectal cancer diagnosis in relation to KRAS mutational status is limited. In a single-center retrospective study, we obtained KRAS and PIK3CA mutational status in a cohort of 153 patients with a first diagnosis of colorectal cancer receiving tumor surgery with curative intent. PIK3CA mutational status was determined by pyrosequencing, and KRAS mutational status was determined by next-generation sequencing. Clinicopathological data and survival data were assessed using patient records and reporting registers. We observed a significant 10-year overall survival benefit in patients with aspirin use and combined wild-type PIK3CA and mutated-KRAS tumors (HR = 0.38; 95% CI = 0.17-0.87; p = 0.02), but not in patients without aspirin use. Our data indicate a benefit of aspirin usage particularly for patients with combined wild-type PIK3CA and mutated-KRAS tumor characteristics.
| S-EPMC8507980 | biostudies-literature
Project description:Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.
| S-EPMC11210231 | biostudies-literature
Project description:Mutations in the oncogenic PIK3CA gene are found in 10-20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA-mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA-mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA-mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome- or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC.
| S-EPMC4649844 | biostudies-other
Project description:This study was designed to determine how aspirin influences the growth kinetics and characteristics of cultured colorectal cancer cells that harbor a variety of different mutational backgrounds, including PIK3CA- and KRAS-activating mutations, and the presence or absence of microsatellite instability. Colorectal cancer cell lines (HCT116, HCT116 + Chr3/5, RKO, SW480, HCT15, CACO2, HT29, and SW48) were treated with pharmacologically relevant doses of aspirin (0.5-10 mmol/L) and evaluated for proliferation and cell-cycle distribution. These parameters were fitted to a mathematical model to quantify the effects and understand the mechanism(s) by which aspirin modifies growth in colorectal cancer cells. We also evaluated the effects of aspirin on key G0-G1 cell-cycle genes that are regulated by the PI3K-Akt pathway. Aspirin decelerated growth rates and disrupted cell-cycle dynamics more profoundly in faster growing colorectal cancer cell lines, which tended to be PIK3CA mutants. Additionally, microarray analysis of 151 colorectal cancer cell lines identified important cell-cycle regulatory genes that are downstream targets of PIK3 and were also dysregulated by aspirin treatment (PCNA and RB1). Our study demonstrated what clinical trials have only speculated, that PIK3CA-mutant colorectal cancers are more sensitive to aspirin. Aspirin inhibited cell growth in all colorectal cancer cell lines regardless of mutational background, but the effects were exacerbated in cells with PIK3CA mutations. Mathematical modeling combined with bench science revealed that cells with PIK3CA-mutations experience significant G0-G1 arrest and explains why patients with PIK3CA mutant colorectal cancers may benefit from aspirin use after diagnosis. Cancer Prev Res; 10(3); 208-18. ©2017 AACR.
| S-EPMC5337164 | biostudies-literature
Project description:In colorectal cancer, mutation of KRAS (RASMUT) reduces therapeutic options, negatively affecting prognosis of the patients. In this setting, administration of CDK4/6-inhibitors, alone or in combination with other drugs, is being tested as promising therapeutic strategy. Identifying sensitive patients and overcoming intrinsic and acquired resistance to CDK4/6 inhibition represent still open challenges, to obtain better clinical responses. Here, we investigated the role of the CDK inhibitor p27kip1 in the response to the selective CDK4/6-inhibitor Palbociclib, in colorectal cancer. Our results show that p27kip1 expression inversely correlated with Palbociclib response, both in vitro and in vivo. Generating a model of Palbociclib-resistant RASMUT colorectal cancer cells, we observed an increased expression of p27kip1, cyclin D, CDK4 and CDK6, coupled with an increased association between p27kip1 and CDK4. Furthermore, Palbociclib-resistant cells showed increased Src-mediated phosphorylation of p27kip1 on tyrosine residues and low doses of Src inhibitors re-sensitized resistant cells to Palbociclib. Since p27kip1 showed variable expression in RASMUT colorectal cancer samples, our study supports the possibility that p27kip1 could serve as biomarker to stratify patients who might benefit from CDK4/6 inhibition, alone or in combination with Src inhibitors.
| S-EPMC8519959 | biostudies-literature
Project description:Ferroptosis, a new form of regulated cell death triggered by the iron-dependent peroxidation of phospholipids, is associated with cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. Aspirin is a widely used non-steroidal anti-inflammatory drug (NSAID) and has been reported to show therapeutic benefit in cancers harboring oncogenic PIK3CA, which encodes the catalytic p110α subunit of phosphoinositide 3-kinase (PI3K). In this study, we found that aspirin sensitized cancer cells harboring oncogenic activation of PIK3CA to ferroptosis induction. Mechanistically, aspirin inhibited protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, suppressed downstream sterol regulatory element-binding protein 1 (SREBP-1) expression, and attenuated stearoyl-CoA desaturase-1 (SCD1)-mediated lipogenesis of monounsaturated fatty acids, thus promoting RSL3-induced ferroptosis in colorectal cancer (CRC) cells. Moreover, genetic ablation of SREBP-1 or SCD1 conferred cancer cells greater sensitivity to ferroptosis induction. Conversely, ectopic expression of SREBP-1 or SCD1 restored ferroptosis resistance in CRC cells and abolished the effect of aspirin on RSL3-induced cytotoxicity. Additionally, the synergistic effects of aspirin and RSL3 were confirmed in a xenograft mouse model. The combined use of aspirin and RSL3 resulted in significant tumor suppression. Our work demonstrated that aspirin enhanced the cytotoxic effect of RSL3 in PIK3CA-mutant cancers, and the combination of aspirin and ferroptosis inducer displayed promising therapeutic effects in cancer treatment.
| S-EPMC9389304 | biostudies-literature
Project description:Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA-mutated CRC.Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression.From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34-92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant.Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA-mutated CRC patients. Prospective evaluation of this relationship is warranted.
| S-EPMC4743650 | biostudies-literature
Project description:Many colorectal cancers (CRCs) develop in genetically susceptible individuals most of whom are not carriers of germ line mismatch repair or APC gene mutations and much of the heritable risk of CRC appears to be attributable to the co-inheritance of multiple low-risk variants. The accumulated experience to date in identifying this class of susceptibility allele has highlighted the need to conduct statistically and methodologically rigorous studies and the need for the multi-centre collaboration. This has been the motivation for establishing the COGENT (COlorectal cancer GENeTics) consortium which now includes over 20 research groups in Europe, Australia, the Americas, China and Japan actively working on CRC genetics. Here, we review the rationale for identifying low-penetrance variants for CRC and the current and future challenges for COGENT.
| S-EPMC3269000 | biostudies-literature