Chemotherapy and Radiotherapy Downregulate the Activity and Expression of DNA Methyltransferase and Enhance Bcl-2/E1B-19-kDa Interacting Protein-3-Induced Apoptosis in Human Colorectal Cancer Cells

Abstract

Bcl-2/E1B 19-kDa interacting protein 3 (BNIP3) is a proapoptotic protein whose expression level is often low in colorectal cancer (CRC) cells due to the BNIP3 gene promoter DNA methylation by DNA methyltransferase (DNMT). It is known that chemotherapy and radiotherapy suppress CRC through inducing tumor apoptosis. However, the molecular mechanisms underlying chemotherapy and radiotherapy-induced apoptosis of CRC cells are not well defined. In this study, we observed that the expression level of BNIP3 in colon cancer cells was significantly increased by treatment with therapeutic agents and radiation in vitro. The BNIP3 protein level in CRC tissues from patients who received preoperative concurrent chemotherapy was significantly higher than in those who received surgery alone. Furthermore, treatment with chemotherapeutic agents and radiation significantly decreased the DNMT1 expression level and enzymatic activity. Both expression level and activity of DNMT1 were inversely correlated with the expression level of BNIP3 in colon carcinoma cells after treatment with chemotherapeutic agents and radiation. Consistent with increased BNIP3 expression, chemotherapeutic agents and radiation induced colon carcinoma cell apoptosis in a dose-dependent manner. Based on these observations, we conclude that chemotherapy and radiotherapy inhibit DNMT1 expression to upregulate BNIP3 expression to promote CRC cell apoptosis. And, BNIP3 may play a role in the caspase-dependent apoptosis pathways, mainly during treatment with chemotherapy and radiotherapy.

RBBP6 increases radioresistance and serves as a therapeutic target for preoperative radiotherapy in colorectal cancer

“…Apoptosis is the primary mechanism for the death of colorectal cancer cells induced by radiotherapy . In the course of radiotherapy, several apoptotic signaling pathways could be involved and the resistance to radiation may result from disruption of the pathways .…”

Epigenetics and Colorectal Cancer Pathogenesis

“…Thus apoptosis mediators are critically important for 5-FU sensitivity. Several apoptosis regulatory genes, including Bik, BNIP3 and DAPK , have been shown to be silenced by their promoter DNA methylation in CRC cells [262,263,264]. Furthermore, it was observed that the response rate to 5-FU therapy is significantly lower in CRC patients with methylation of either DAPK or BNIP3 , or both, than in those without methylation.…”

“…Furthermore, it was observed that the response rate to 5-FU therapy is significantly lower in CRC patients with methylation of either DAPK or BNIP3 , or both, than in those without methylation. Both progression-free survival and overall survival time are significantly shorter in patients with methylation of either or both of these genes than in those without [264]. Therefore, it is apparent that CRC cells use DNA methylation to silence BNIP3 and DAPK to acquire an apoptosis-resistant phenotype to resist 5-FU, and thereby specific targeting of these DNA methylation-silenced genes might potentially be an effective and yet less toxic approach to overcome CRC resistance to 5-FU.…”

DNA Methylation and Apoptosis Resistance in Cancer Cells

“…Survival time of patients with BNIP3 methylation was shorter than in absence of methylation in gastric tumors, whereas no such association could be found in breast tumors [28]. In addition, patients with methylation exhibited resistance to chemotherapy compared to patients with no methylation, suggesting that methylation of BNIP3 is a predictive factor in the prognosis and response to treatment in colorectal cancer patients [118,119,120]. …”