p53 restoration can overcome cisplatin resistance through inhibition of Akt as well as induction of Bax

Kim,Chae Won; Lu,Jing Nan; Go,Se-Il; Jung,Ji Hyun; Yi,Sang Mi; Jeong,Jae-Hoon; Hah,Young-Sool; Han,Myung Shin; Park,Jeong Woo; Lee,Won Sup; Min,Young Joo

doi:10.3892/ijo.2013.2070

p53 restoration can overcome cisplatin resistance through inhibition of Akt as well as induction of Bax

Authors:
- Chae Won Kim
- Jing Nan Lu
- Se-Il Go
- Ji Hyun Jung
- Sang Mi Yi
- Jae-Hoon Jeong
- Young-Sool Hah
- Myung Shin Han
- Jeong Woo Park
- Won Sup Lee
- Young Joo Min
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Affiliations: Department of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea, Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Gyeongnam Regional Cancer Center, Gyeongsang National University Hospital, Jinju, Republic of Korea, Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
Published online on: August 21, 2013 https://doi.org/10.3892/ijo.2013.2070
Pages: 1495-1502

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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.

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