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Altered apoptotic gene expression and acquired apoptotic resistance in cadmium‐transformed human prostate epithelial cells
Author(s) -
Achanzar William E.,
Webber Mukta M.,
Waalkes Michael P.
Publication year - 2002
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.10106
Subject(s) - apoptosis , prostate , gene , gene expression , biology , cancer research , epithelium , pathology , medicine , cancer , genetics
BACKGROUND Cadmium is a suspected prostatic carcinogen, although the underlying mechanisms are unclear. To investigate these mechanisms, we performed molecular comparisons between the cadmium‐transformed prostate epithelial cell line CTPE and the nontumorigenic parental line RWPE‐1. METHODS Gene expression patterns were compared by using cDNA arrays, RNase protection assays, and Western blots. Apoptosis was analyzed by using flow cytometry to quantify apoptotic nuclei and an enzyme‐linked immunosorbent assay method to measure DNA fragmentation. Caspase‐3 activity was measured colorimetrically. RESULTS Among the genes down‐regulated in CTPE cells were those encoding several members of the caspase family of apoptotic proteases as well as the apoptotic regulator Bax. Ribonuclease protection assays confirmed global down‐regulation of caspase gene expression in CTPE. Decreased Bax expression in CTPE was confirmed by Western blots, which also revealed increased expression of anti‐apoptotic Bcl‐2. Consistent with these changes, CTPE cells exhibited increased resistance to apoptosis induced by cadmium, cisplatin, and etoposide. CTPE cells also exhibited lower caspase‐3 activity vs. RWPE‐1 after etoposide treatment. CONCLUSIONS CTPE cells exhibited altered expression of important apoptotic regulators as well as resistance to several apoptotic stimuli. We hypothesize that acquired apoptotic resistance may be a key aspect of cadmium‐induced malignant transformation of prostate epithelial cells and that this may contribute to both tumor initiation and the acquisition of aggressive characteristics subsequent to tumor formation. Prostate 52:236–244, 2002. © 2002 Wiley‐Liss, Inc.