Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair

Hsu, Jui-Ling; Leong, Pui-Kei; Ho, Yunn-Fang; Hsu, Lih-Ching; Lu, Pin-Hsuan; Chen, Ching-Shih; Guh, Jih-Hwa

doi:10.1016/j.canlet.2012.01.004

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Volume 319, Issue 2 , Pages 214-222, 28 June 2012

Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair

Jui-Ling Hsu
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei 100, Taiwan
Pui-Kei Leong
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei 100, Taiwan
Yunn-Fang Ho
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei 100, Taiwan
Lih-Ching Hsu
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei 100, Taiwan
Pin-Hsuan Lu
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei 100, Taiwan
Ching-Shih Chen
- Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
Jih-Hwa Guh
- School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Road, Taipei 100, Taiwan
- Corresponding author. Tel.: +886 2 3393 7561; fax: +886 2 2391 9098.

Received 1 November 2011; received in revised form 26 December 2011; accepted 10 January 2012. published online 02 February 2012.

Abstract

The knockdown of Pim-1 or inhibition of Pim-1 activity significantly increased γ-H2A.X expression. The effect was correlated to apoptosis and was attributed to the inhibition of nonhomologous DNA-end-joining (NHEJ) repair activity supported by the following observations: (1) inhibition of ATM and DNA-PKcs activities, (2) down-regulation of Ku expression and nuclear localization and (3) decrease of DNA end-binding of both Ku70 and Ku80. The data suggest that Pim-1 plays a crucial role in the regulation of NHEJ repair. In the absence of Pim-1, the ability of DNA repair significantly decreases when exposed to paclitaxel, leading to severe DNA damage and apoptosis.

Keywords: Pim-1, Paclitaxel, H2A.X phosphorylation, NHEJ DNA repair, Prostate cancers