title: p53 restoration can overcome cisplatin resistance through inhibition of Akt as well as induction of Bax.
abstract: Cisplatin (CDDP) is a chemotherapeutic agent that is widely used to treat many cancers. However, initial resistance to CDDP is a serious problem in treating cancers. In this study, in order to develop an approach to overcome resistance to CDDP, we investigated the difference in apoptotic processes between CDDP-sensitive cells and CDDP-resistant cells. By screening with CDDP sensitivity tests, we chose SNU-16 cells which are relatively resistant to CDDP, and SNU-1 cells which are sensitive to CDDP. We compared the difference between the two cell lines focusing on apoptosis. CDDP-induced reactive oxygen species (ROS) generation significantly induced loss of mitochondrial membrane potential (MMP, ∆Ψm) in SNU-1 cells, but not in SNU-16 cells. In addition, the ratio of Bax to Bcl-2 was increased by CDDP treatment in SNU-1 cells, but not in SNU-16 cells. To augment the loss of MMP, ∆Ψm in SNU-16, we inhibited Akt activity of SNU-16 cells to suppress their anti-apoptotic activity. The inhibition of Akt activity led to suppression of the anti-apoptotic protein XIAP. Akt inhibition slightly enhanced CDDP-induced apoptosis in SNU-16 cells. In addition, we enhanced pro-apoptotic activity by transfecting the cells with the wild-type p53 gene. The induction of wild-type p53 can enhance CDDP-induced apoptosis not only by inducing Bax protein but also by suppressing anti-apoptotic proteins through inhibition of Akt. In conclusion, this study suggests that the primary contributor to resistance to CDDP in SNU-16 cells may well be a failure of induction of apoptosis due to a lack of induction of pro-apoptotic proteins rather than suppression of anti-apoptotic proteins, and that restoration of p53 function can overcome the resistance to CDDP not only by augmenting the pro-apoptotic drive through p53-mediated transcriptional activation but also by inhibiting the anti-apoptotic drive through inhibition of Akt activity.
authors: Department of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
authors: Chae Won
authors: CW
authors: Kim
authors: Jing Nan
authors: JN
authors: Lu
authors: Se-Il
authors: SI
authors: Go
authors: Ji Hyun
authors: JH
authors: Jung
authors: Sang Mi
authors: SM
authors: Yi
authors: Jae-Hoon
authors: JH
authors: Jeong
authors: Young-Sool
authors: YS
authors: Hah
authors: Myung Shin
authors: MS
authors: Han
authors: Jeong Woo
authors: JW
authors: Park
authors: Won Sup
authors: WS
authors: Lee
authors: Young Joo
authors: YJ
authors: Min
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007124:Immunoenzyme Techniques; D053078:Membrane Potential, Mitochondrial; D009154:Mutation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin