Alterations in Gene Transcription by Physiological Stress: A Mechanism for Drug Resistance Through NF-kB Activation

摘要

One of the major limiting factors to the successful treatment of breast cancer is the development of drug resistance. Adverse conditions associated with solid tumor progression, which trigger cellular stress responses, may underlie the mechanisms of intrinsic chemotherapeutic drug resistance. EMT6 mouse mammary tumor cells treated with the chemical stress agent, brefeldin A (BFA) or the physiologic stress, hypoxia develop comparable levels of resistance to the topoisomerase II inhibitor, etoposide. To determine common mechanisms for chemical- and physiologic-induced drug resistance, we have performed expression analysis of stress-treated EMT6 cells. BFA or hypoxia treatment result in enhanced expression of transforming growth factor-beta (TGF- beta) and decreased expression of the platelet-derived growth factor receptor, PDGFRalpha, and the mitogen-activated protein kinase (MAPK), MEK1. Western blot analysis confirms increased TGF-beta protein and reduced PDGFRalpha and phospho- MEK1/2 levels with stress treatment. In vitro studies show treatment with TGF- beta, anti-PDGFRalpha blocking antibodies, or inhibition of MEK1/2 with U0126 treatment are sufficient to cause etoposide resistance. These results provide evidence for TGF-beta activation and down-regulation of the PDGFRalpha/MAPK signaling pathway in the development of tumor drug resistance and suggest that modulation of TGF-beta, PDGFRalpha or the MAPK cascade may enhance the clinical effectiveness of conventional anticancer chemotherapies.