Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and clap1

Ming Yang Wang, Pai Sheng Chen, Ekambaranellore Prakash, Hsing Chih Hsu, Hsin Yi Huang, Ming Tsan Lin, King Jen Chang, Min Liang Kuo

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes metastasis. Chemotherapy response is only transient in most metastatic diseases. In the present study, we examined whether CTGF expression could confer drug resistance in human breast cancer. In breast cancer patients who received neoadjuvant chemotherapy, CTGF expression was inversely associated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability, and resistance to apoptosis on exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) ceDs by antisense CTGF cDNA (MDA231/AS cells) mitigated this drug resistance capacity. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cellular inhibitor of apoptosis protein 1 (cIAPl). Knockdown of Bcl-xL or cIAPl with specific small interfering KNAs abolished the CTGF-mediated resistance to apoptosis induced by the chemotherapeutic agents in MCF7/CTGF cells. Inhibition of extracellular signal-regulated kinase (ERK)-l/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAPl in MCF7/CTGF cells. A neutralizing antibody against integrin α vβ3 significantly attenuated CTGF-mediated ERK1/2 activation and upregulation of Bcl-xL and cIAPl, indicating that the integrin αvβ3/ERKl/2 signaling pathway is essential for CTGF functions. The Bcl-xL level also correlated with the CTGF level in breast cancer patients. We also found that a COOH-terminal domain peptide from CTGF could exert activities similar to full-length CTGF, in activation of ERK1/2, up-regulation of Bcl-xL/cIAPl, and resistance to apoptosis. We conclude that CTGF expression could confer resistance to chemotherapeutic agents through augmenting a survival pathway through ERKl/2-dependent Bcl-xL/cIAPl up-regulation.

Original languageEnglish
Pages (from-to)3482-3491
Number of pages10
JournalCancer Research
Volume69
Issue number8
DOIs
Publication statusPublished - 2009 Apr 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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