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Insulin‐like growth factor‐I promotes multidrug resistance in MCLM colon cancer cells
Author(s) -
Guo YanShi,
Jin GuiFang,
Houston Clifford W.,
Thompson James C.,
Townsend Courtney M.
Publication year - 1998
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199805)175:2<141::aid-jcp3>3.0.co;2-o
Subject(s) - cytotoxic t cell , microbiology and biotechnology , biology , apoptosis , cell culture , multiple drug resistance , programmed cell death , cancer cell , cell growth , transfection , cancer research , cancer , in vitro , biochemistry , drug resistance , genetics
Insulin‐like growth factor‐I (IGF‐I) is known as a potent mitogen for a variety of cell types, including colon cancer cell lines. The objective of this study was to determine the effect of IGF‐I on cell death induced by cytotoxic agents actinomycin D (Act‐D), lovastatin (LOV), and doxorubicin (DOX) in the MCLM mouse colon cancer cell line, and the mechanisms involved. Subconfluent monolayer MCLM cells were treated with IGF‐I (25 ng/ml) for 12 h in serum‐free media. Various concentrations of cytotoxic agents then were added to the cells that were incubated continually at 37°C for 24 h. Cell survival was determined with the MTT (3‐[4‐5‐dimenthylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide) assay, which assesses mitochondrial function in living cells. The mRNA expression for multidrug resistance gene‐I (mdr‐I), c‐H‐ras, and manganese superoxide dismutase (MnSOD) in cells treated with IGF‐I was examined by Northern blot or RNase protection assays. The levels of p‐glycoprotein, a drug efflux pump encoded by the mdr‐I gene, were assessed by Western immunoblotting. Results demonstrated that (1) IGF‐I significantly inhibited the cell death and apoptosis of MCLM cells treated with Act‐D, LOV, or DOX; (2) IGF‐I increased mRNA expression for mdr‐I, c‐H‐ras, and MnSOD; (3) the p‐glycoproteins in cells treated with IGF‐I or stably transfected with c‐H‐ras were elevated when compared with control. These results suggest that IGF‐I protects MCLM cells against death induced by cytotoxic agents; this acquired drug resistance may be mediated by multiple mechanisms, including promoting expression of mdr‐I, c‐H‐ras, and MnSOD; whereas, the p‐glycoprotein level stimulated by IGF‐I may result partly from the increase of c‐H‐ras in the cells. J. Cell. Physiol. 175:141–148, 1998. © 1998 Wiley‐Liss, Inc.