Phosphorylation of Caspase-7 by p21-activated Protein Kinase (PAK) 2 Inhibits Chemotherapeutic Drug-induced Apoptosis of Breast Cancer Cell Lines

Xiang Li,Weihong Wen,Kangdong Liu,Feng Zhu,Margarita Malakhova,Cong Peng,Tingting Li,Hong-Gyum Kim,Weiya Ma,Yong Yeon Cho,Ann M Bode,Ziming Dong,Zigang Dong

doi:10.1074/jbc.m111.236596

Abstract

p21-activated kinase (PAK) 2, a member of the PAK family of serine/threonine protein kinases, plays an important role in physiological processes such as motility, survival, mitosis, and apoptosis. However, the role of PAK2 in resistance to chemotherapy is unclear. Here we report that PAK2 is highly expressed in human breast cancer cell lines and human breast invasive carcinoma tissue compared with a human non-tumorigenic mammary epithelial cell line and adjacent normal breast tissue, respectively. Interestingly, we found that PAK2 can bind with caspase-7 and phosphorylate caspase-7 at the Ser-30, Thr-173, and Ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. Our data indicate that highly expressed PAK2 mediates chemotherapeutic resistance in human breast invasive ductal carcinoma by negatively regulating caspase-7 activity.

Highlights

The p21-activated kinase (PAK) family of serine/threonine kinases, which were initially identified as binding partners of the Rho GTPases Cdc42 and Rac1 [11], plays an important role in physiological processes such as motility, survival, mitosis, apoptosis, and hormone signaling [12]
The results revealed that the PAK2 expression level was significantly higher in breast invasive ductal carcinoma tissues with a median expression level of 43.67 compared with PAK2 expression in adjacent normal tissues, which had a median score of 17.47 (Fig. 1A)
The expression levels of PAK2 in different breast cancer cell lines were determined, and the results indicated that the expression level of PAK2 was higher in the MCF-7, SKBR-3, and MDA-MB-468 breast cancer cell lines compared with MCF-10A, a human non-tumorigenic mammary epithelial cell line (Fig. 1B)

Summary

Introduction

This suggests that the expression and modification of growth factor receptors and their downstream kinases might correspond with breast cancer chemotherapy resistance [10]. The PAK family of serine/threonine kinases, which were initially identified as binding partners of the Rho GTPases Cdc and Rac1 [11], plays an important role in physiological processes such as motility, survival, mitosis, apoptosis, and hormone signaling [12]. PAK1 is known to promote cell survival through its phosphorylation of Bad on Ser-112 and Ser-136 [14]. PAK1 phosphorylates the estrogen receptor at Ser-305, leading to increased cyclin D1 expression and hormone independence of breast cancer cells [15, 16]. Our results suggest that PAK2 is a novel target of chemotherapy for breast cancer

Methods

Results

Conclusion