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p53 interferes with microtubule-stabilizing agent-induced apoptosis in prostate and colorectal cancer cells

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Taxanes are microtubule-stabilizing agents that have anticancer activity against several types of human solid tumors. Although the primary mechanism of action of these drugs is well understood, the signaling pathways that confer resistance to these agents in certain types of cancer remain poorly understood. In particular, the association of p53 with the mechanism(s) of taxane-mediated cell death is still controversial. In this study, we showed that p53 has a profound inhibitory effect on docetaxel (Doc)-induced apoptosis in prostate and colorectal cancer cells and that caspases play a critical role in this process. Doc induced prostate cancer cell apoptosis at high levels in p53-null PC3 cells, at intermediate levels in p53-mutant DU145 cells and at low levels in p53 wild-type LNCaP cells. While transient overexpression of p53 in PC3 cells suppressed Doc-induced apoptosis, knockdown of p53 in LNCaP cells increased apoptosis. This finding was further confirmed using an isogenic pair of colorectal cancer cell lines, HCT-116 p53-/- and p53+/+, indicating that p53 inhibits induction of apoptosis by Doc. To our knowledge, this is the first report describing that chemical or genetic knockout of p53 enhances the susceptibility of both prostate and colorectal cancer cells to Doc-induced apoptosis. These results may suggest an approach to stratify patients for regimens involving Doc.
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Document Type: Research Article

Affiliations: 1: Department of Anatomy and Cell Biology, Dong-A University, Busan 602-714, Republic of Korea 2: Mitochondria Hub Regulation Center, Dong-A University, Busan 602-714, Republic of Korea 3: Department of Biochemistry, Dong-A University, Busan 602-714, Republic of Korea 4: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongnam 626-870, Republic of Korea 5: Department of Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea 6: Medical Research Science Center, Dong-A University, Busan 602-714, Republic of Korea

Publication date: January 1, 2013

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  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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