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CTGF increases drug resistance to paclitaxel by upregulating survivin expression in human osteosarcoma cells

By Hsiao-Chi Tsai, Chun-Yin Huang, Hong-Lin Su and Chih-Hsin Tang

Abstract

Osteosarcoma is the most common primary malignant tumor, and its treatments require more effective therapeutic approaches. Paclitaxel has a broad range of antitumor activities, including apoptosis-inducing effects. However, the majority of tumors in patients with advanced cancer eventually develop chemoresistance. Connective tissue growth factor (CTGF) is a secreted protein that modulates the invasiveness of certain human cancer cells by binding to integrins. However, the effect of CTGF in paclitaxel-mediated chemotherapy is unknown. Here, we report that the expression of CTGF in osteosarcoma patients was significantly higher than that of the CTGF expression in normal bone tissues. Overexpression of CTGF increased the resistance to paclitaxel-mediated cell apoptosis. In contrast, knockdown of CTGF expression by CTGF shRNA increased the chemotherapeutic effect of paclitaxel. In addition, CTGF increased resistance to paclitaxel-induced apoptosis through upregulation of survivin expression. Moreover, the AMP-activated protein kinase (AMPK)-dependent nuclear factor kappa B (NF-κB) pathway mediated paclitaxel-increased chemoresistance and survivin expression. In a mouse xenograft model, overexpression of CTGF promoted resistance to paclitaxel. In contrast, knockdown of CTGF expression increased the therapeutic effect of paclitaxel in this model. In conclusion, our data indicate that CTGF might be a critical oncogene of human osteosarcoma involved in resistance to paclitaxel treatment

Topics: CTGF, Chemotherapy, Osteosarcoma, Paclitaxel, Survivin, Animals, Antineoplastic Agents, Phytogenic, Cell Line, Tumor, Connective Tissue Growth Factor, Drug Resistance, Neoplasm, Humans, In Situ Nick-End Labeling, Inhibitor of Apoptosis Proteins, Mice, Mice, Nude, Osteosarcoma, Paclitaxel, Real-Time Polymerase Chain Reaction, Up-Regulation
Year: 2015
DOI identifier: 10.1016/j.bbamcr.2014.01.007
OAI identifier: oai:ir.lib.nchu.edu.tw:11455/86464
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