Tamoxifen accelerates proteasomal degradation of O6-methylguanine DNA methyltransferase in human cancer cells.

Abstract

Tamoxifen, a synthetic triphenyl-ethylene compound, is a member of a class of anticancer drugs known as selective estrogen receptor modulators. It may block tumor growth by mimicking estrogen and binding to the estrogen receptors, preventing cancerous growth. Clinical studies have demonstrated that a combination chemo/hormonal therapy regimen with tamoxifen and O(6)-alkylating drugs increased the tumor response rate in cancer patients. The mechanism of action of this combined regimen remains undefined. In this study, we demonstrated that treatment of human colorectal HT-29 carcinoma cells with tamoxifen decreased the repair activity and expression level of O(6)-methylguanine DNA methyltransferase (MGMT) protein in a concentration- and time-dependent manner. This inhibition was also shown in other malignant human cells, regardless of their estrogen receptor status. Furthermore, MGMT inactivation by tamoxifen was associated with a significantly increased susceptibility of cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). No alteration in MGMT mRNA levels was observed in tamoxifen-treated cells. The half-life of MGMT protein was markedly decreased in the presence of tamoxifen. Tamoxifen-induced MGMT degradation could be blocked by MG-132, a proteasome inhibitor. An increased level of ubiquitinated MGMT protein was found after tamoxifen treatment. We conclude that tamoxifen decreased the MGMT protein level by accelerating protein degradation through the ubiquitin-dependent proteasomal pathway. These findings provide a strong rationale for combined chemo/hormonal therapy with tamoxifen and BCNU in the treatment of human cancers.

• Authors: Ching-Chuan Kuo, Jin-Fen Liu, Her-Shyong Shiah, Li-Chen Ma, Jang-Yang Chang
• Journal: International journal of cancer (Int J Cancer) Vol. 121 Issue 10 Pg. 2293-300 (Nov 15 2007) ISSN: 1097-0215 [Electronic] United States
• PMID: 17597106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• RNA, Messenger
• Ubiquitin
• Tamoxifen
• O(6)-Methylguanine-DNA Methyltransferase
• Proteasome Endopeptidase Complex
• Carmustine

Topics

• Carmustine (toxicity)
• Cell Line, Tumor
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Inhibitory Concentration 50
• Kinetics
• Neoplasms (enzymology, pathology)
• O(6)-Methylguanine-DNA Methyltransferase (genetics, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• RNA, Messenger (genetics)
• Tamoxifen (toxicity)
• Ubiquitin (metabolism)