title: p53 interferes with microtubule-stabilizing agent-induced apoptosis in prostate and colorectal cancer cells.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University, Busan, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Chung
authors.forename: Seung Gee
authors.initials: SG
authors.lastname: Lee
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Kim
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Jeanho
authors.initials: J
authors.lastname: Yun
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Park
authors.forename: Byeong Gee
authors.initials: BG
authors.lastname: Kim
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008870:Microtubules / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D020169:Caspases