ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38

Molecular Cancer Therapeutics - Tập 12 Số 12 - Trang 2782-2791 - 2013
Yunfei Zhou1,2, Lakshmi Reddy Bollu1,2, Federico Tozzi1,2, Xiangcang Ye1,2, Rajat Bhattacharya1,2, Guang Gao1,2, Elizabeth Dupre1,2, Ling Xia1,2, Jia Lu1,2, Fan Fan1,2, Seth Bellister1,2, Lee M. Ellis1, Weihua Zhang1,2
1Authors' Affiliations: Departments of 1Cancer Biology and 2Surgical Oncology, The University of Texas MD Anderson Cancer Center; and 3Department of Biology and Biochemistry, University of Houston, Houston, Texas
2Department of Biology and Biochemistry, University of Houston, Houston, Texas

Tóm tắt

AbstractCombination chemotherapy is standard for metastatic colorectal cancer; however, nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may enable identification of novel targets and more effective therapy. Irinotecan is commonly used in first- and second-line therapy for patients with metastatic colorectal cancer, with the active metabolite being SN38. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance. Using Oncomine and unbiased proteomic profiling, we found that ATP citrate lyase (ACLy), the first-step rate-limiting enzyme for de novo lipogenesis, was upregulated in colorectal cancer compared with its levels in normal mucosa and in chemoresistant colorectal cancer cells compared with isogenic chemo-naïve colorectal cancer cells. Overexpression of exogenous ACLy by lentivirus transduction in chemo-naïve colorectal cancer cells led to significant chemoresistance to SN38 but not to 5-fluorouracil or oxaliplatin. Knockdown of ACLy by siRNA or inhibition of its activity by a small-molecule inhibitor sensitized chemo-naïve colorectal cancer cells to SN38. Furthermore, ACLy was significantly increased in cancer cells that had acquired resistance to SN38. In contrast to chemo-naïve cells, targeting ACLy alone was not effective in resensitizing resistant cells to SN38, due to a compensatory activation of the AKT pathway triggered by ACLy suppression. Combined inhibition of AKT signaling and ACLy successfully resensitized SN38-resistant cells to SN38. We conclude that targeting ACLy may improve the therapeutic effects of irinotecan and that simultaneous targeting of ACLy and AKT may be warranted to overcome SN38 resistance. Mol Cancer Ther; 12(12); 2782–91. ©2013 AACR.

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Molecular Cancer Therapeutics

Tập 12 Số 12

2782-2791

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