Upregulation of CYP2S1 by oxaliplatin is associated with p53 status in colorectal cancer cell lines

Abstract

Oxaliplatin displays a wide spectrum of antitumor activities and is widely used in the treatment of metastatic colorectal cancer (CRC). However, tumor responses to this agent are variable, and the underlying mechanisms are poorly understood. In the present study, oxaliplatin was found to strongly inhibit the growth of HCT116 cells harboring wild-type p53 but to only weakly inhibit SW480 cells, HT29 cells or p53−/− HCT116 cells, which all lack p53 expression. Administration of oxaliplatin significantly induced p53 accumulation and enhanced expression of CYP2S1 in HCT116 cells with wild-type p53. CYP2S1 knockdown conferred a cell survival advantage after oxaliplatin treatment to cells harboring wild-type p53 in vitro and in vivo. Interestingly, enzyme immunoassays, TOPFlash/FOPFlash reporter activity assays and western blotting analysis demonstrated oxaliplatin-mediated downregulation of PGE2 and Wnt/β-catenin signaling in a manner dependent on p53. Moreover, oxaliplatin treatment of mice with subcutaneous tumor xenografts drastically reduced the volume of wild-type p53 HCT116 tumors but had no effect on isogenic p53−/− HCT116 tumors. These results suggest that oxaliplatin exerts its inhibitory effects in human CRC cells via upregulation of CYP2S1 expression in a p53-dependent manner.

High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy

“…24,25 For metformin analysis, the cells were treated (four wells per treatment) with various d -(+)-glucose concentrations (5, 10, or 15 mM) for 24 h, and then with different concentrations (0, 1, or 5 mM) of metformin for 22 h. For the oxaliplatin chemotoxicity analysis, the cells were treated with or without oxaliplatin (HCT-116, SW480, and SW620: 5 μM; HT-29: 10 μM). 26 For the oxaliplatin and metformin chemotoxicity analysis, the cells were treated with various d -(+)-glucose concentrations (5, 10, or 15 mM) for 24 h, then with different concentrations of metformin (0, 1, or 5 mM) for 24 h, followed by oxaliplatin (HCT-116, SW480, and SW620: 5 μM; HT-29: 10 μM) for 2 h, and finally recovered within different concentrations of metformin (0, 1, or 5 mM) for another 22 h. To determine cell proliferation, the cells were further incubated using a 1/10 volume of WST-1 reagent (Roche Diagnostics Corp., Indianapolis, IN, USA) for 2 h at 37°C before measuring absorbance using a spectrophotometer at 450 nm. The assay was performed three times for each cell line.…”

Akkermansia Muciniphila Potentiates the Antitumor Efficacy of FOLFOX in Colon Cancer

“…Oxaliplatin and Calcium Folinate Injection were both obtained from Aosaikang (Jiangsu, China), and 5-FU Injection was obtained from SunRise (Shanghai, China). Oxaliplatin and FOLFOX Injection were prepared according to clinical guidelines as well as existing studies (Iida et al, 2013;Yang et al, 2016). Chemicals including O-Methoxyamine hydrochloride, N-methyl-N-trifluoroacetamide (MSTFA) and cortisone acetate were purchased from Sigma-Aldrich (St.Louis, MO, United States).…”

“…When the tumors reached to about 100 mm 3 , mice were randomly allocated to one of the groups (day 0), i.e., model for oxaliplatin (MO, n 8), oxaliplatin treatment (Oxaliplatin, n 27), model for FOLFOX (MF, n 6), FOLFOX treatment (FOLFOX, n 33). Based on previous studies, oxaliplatin (10 mg/kg) was intraperitoneally administrated twice a week (Yang et al, 2016), and FOLFOX (oxaliplatin 6mg/kg, 2 h after 5-FU 50 mg/kg and Calcium Folinate 90m g/kg treatment) was intraperitoneally administrated once a week (Robinson et al, 2013;Limani et al, 2016). MO and MF individuals were treated with corresponding vehicles.…”

Metabolism-associated genes in occurrence and development of gastrointestinal cancer: Latest progress and future prospect

“…CYP2S1 regulates CRC growth via the PGE2-mediated activation of the β-catenin signaling pathway[ 65 ]. Upregulation of CYP2S1 is associated with p53 status in CRC cell lines[ 103 ]. The p53 mutation is found in approximately 60% of CRC patients.…”