Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells

Abstract

The clinical efficacy of colorectal tumor treatment is restricted due to platinum agent resistance. Translesion DNA synthesis (TLS) has been shown to contribute to this resistance; however, the exact molecular mechanism remains unknown. The present study aimed to investigate the possible function of the core of the TLS polymerase mitotic arrest deficient 2 like 2 (MAD2L2) in drug sensitivity, in order to provide a treatment rationale for platinum-based chemotherapy in colon cancer. In the present study, MAD2L2 was knocked down using MAD2L2-specific small interfering (si)RNA. HCT116 and SW620 cells were treated with oxaliplatin and MG132; oxaliplatin is a platinum compound that induces DNA damage and MG132 is a potent proteasome inhibitor. Cell viability was determined using an MTT assay. Cell apoptosis was examined via flow cytometry and TUNEL assay. The activity of proteasome 26S subunit, non-ATPase 13 (PSMD13) was detected using ELISA, while the expression levels of apoptotic-related proteins were detected via western blotting. The results demonstrated that cells treated with oxaliplatin or MG132 alone had decreased viability, but a synergistic effect was not observed after co-treatment. In addition, the knockdown of MAD2L2 caused by siMAD2L2 or oxaliplatin treatment increased the expression levels of the pro-apoptotic proteins Bax and Bak and decreased the expression levels of the anti-apoptotic protein Bcl-2, compared with the negative control group. Moreover, MG132 alleviated the decrease in MAD2L2 expression, while reducing siMAD2L2-induced cell apoptosis. These results indicate that oxaliplatin promotes siMAD2L2-induced apoptosis in colon cancer cells. This process was associated with the Bcl-2 and ubiquitin-proteasome pathway. Overall, the present study provides a theoretical basis for improving the clinical efficacy of colon cancer by combining chemotherapy and gene therapy.

REV7 in Cancer Biology and Management

“…Hypersensitivity to DNA-damaging agents such as cisplatin, carboplatin, melphalan, chlorethamine, doxorubicin, mitomycin c, or γ-irradiation, but not to H 2 O 2 , 5FU, taxol, or vincristine, decreased spontaneous and damage-induced mutation frequency, accumulation of DSBs and increased chromosomal aberrations after DNA damage, and suppressed cisplatin-induced SCE are promoted by REV7 depletion in nasopharyngeal carcinoma cells [ 61 ]. REV7 suppression also sensitizes malignant melanoma, TGCT, and colon cancer cells to cisplatin, doxorubicin, or oxaliplatin, and sensitizes gliomas and esophageal squamous cell carcinoma (SCC) cells to IR [ 86 , 90 , 91 , 101 ]. In addition, tumor-bearing mouse experiments with REV7 -depleted cancer cells also demonstrated suppressed cell proliferation, increased apoptotic cells, and enhanced sensitivity to cisplatin in vivo in ovarian cancer and TGCT cells [ 87 , 91 ].…”

Molecular Pathogenesis of Colorectal Cancer with an Emphasis on Recent Advances in Biomarkers, as Well as Nanotechnology-Based Diagnostic and Therapeutic Approaches

“…Oxaliplatin’s cytotoxic effects, on the other hand, are still poorly studied in detail. Many chemotherapeutic drugs, including oxaliplatin, have been demonstrated to cause apoptosis in tumour cells [ 111 ]. Since a medication’s cellular target is dependent on the accumulation in cancer cells, the clinical efficacy of oxaliplatin may be influenced by variables that regulate its accumulation due to its expression by tumour cells or by biological barriers that impact drug disposition.…”

PSMD13 is a prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

“…Therefore, the ubiquitin host system cooperates the immune system to ght bacteria 9 . Newly research has found that enhancing the lives of PSMD13 protein may promote apoptosis and increase the expression of Bax and Bak, while the expression of Bcl2 is, on the contrary, thus expanding the apoptosis rate of colon cancer cells 10 . PSMD13 regulates the production of in ammatory mediators, and the production of INOS, COX-2, NO, and prostaglandin Escherichia 2 substantially decreased after PSMD13 gene knockout 7 .…”