DBC2 resistance is achieved by enhancing 26S proteasome-mediated protein degradation.
Tumor suppressor gene DBC2 stops growth of tumor cells through regulation of CCND1. Interference of CCND1 down-regulation prevented growth arrest caused by DBC2 [T. Yoshihara, D. Collado, M. Hamaguchi, Cyclin D1 down-regulation is essential for DBC2's tumor suppressor function, Biochemical and biophysical research communications 358 (2007) 1076-1079]. It was also noted that DBC2 resistant cells eventually arose after repeated induction of DBC2 with muristerone A treatment [M. Hamaguchi, J.L. Meth, C. Von Klitzing, W. Wei, D. Esposito, L. Rodgers, T. Walsh, P. Welcsh, M.C. King, M.H. Wigler, DBC2, a candidate for a tumor suppressor gene involved in breast cancer, Proc. Natl. Acad. Sci. USA 99 (2002) 13647-13652]. In order to elucidate the mechanism of resistance acquisition, we analyzed DBC2 sensitive and resistant cells derived from the same progenitor cells (T-47D). We discovered that DBC2 protein was abundantly expressed in the sensitive cells when DBC2 was induced. In contrast, it was undetectable by western blot analysis in the resistant cells. We confirmed that the inducible gene expression system was responsive in both cells by detecting induced GFP. Additionally, inhibition of 26S proteasome by MG132 revealed production of DBC2 protein in the resistant cells. These findings indicate that the resistant T-47D cells survive DBC2 induction by rapid destruction of DBC2 through 26S proteasome-mediated protein degradation.
Collado
Denise
D
Department of Biological Sciences, Fordham University, 441 E Fordham Road, Larkin Hall, Bronx, NY 10458, USA.
Yoshihara
Takashi
T
Hamaguchi
Masaaki
M
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D018014:Gene Transfer Techniques; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D019076:Transgenes; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; C497336:RHOBTB2 protein, human; D025521:Tumor Suppressor Proteins; C055348:muristerone A; D004441:Ecdysterone; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D019204:GTP-Binding Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde