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.
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.
Department of Abdomen Oncology, Cancer Center of West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China.
Qian
Q
Deng
Chun-mei
CM
Huang
Ni
N
Chen
Li
L
Li
Xiao-dong
XD
Wang
Wen
W
Zhang
Feng
F
Bi
Qiu-lin
QL
Tang
Zhi-ping
ZP
Li
Wei
W
Wang
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D012189:Retrospective Studies; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D020169:Caspases