Affiliations 

  • 1 Graduate Institute of Biomedical Sciences, Division of Biotechnology College of medicine, Chang Gung University,Tao-Yuan, Taiwan, Republic of China
  • 2 Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China
  • 3 Graduate Institute of Biomedical Sciences, Division of Biotechnology College of medicine, Chang Gung University,Tao-Yuan, Taiwan, Republic of China; Department of Medical Biotechnology and Laboratory Science, College of medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China; Molecular Medicine Research Center, College of medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China
  • 4 Department of Medical Biotechnology and Laboratory Science, College of medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China
  • 5 Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia
  • 6 Graduate Institute of Biomedical Sciences, Division of Biotechnology College of medicine, Chang Gung University,Tao-Yuan, Taiwan, Republic of China; Department of Medical Biotechnology and Laboratory Science, College of medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China; Molecular Medicine Research Center, College of medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. Electronic address: kchong@mail.cgu.edu.tw
Int J Biochem Cell Biol, 2014 Aug;53:55-65.
PMID: 24814288 DOI: 10.1016/j.biocel.2014.04.011

Abstract

Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human uterus sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.