title: ATP citrate lyase mediates resistance of colorectal cancer cells to SN38.
abstract: Combination 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.
authors.affiliation: Corresponding Authors: Zhang Weihua, Department of Biology and Biochemistry, College of Natural Sciences and Mathematics University of Houston, 4800 Calhoun Rd, HSC358, Houston, TX 77204. wzhang13@uh.edu.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lakshmi Reddy
authors.initials: LR
authors.lastname: Bollu
authors.forename: Federico
authors.initials: F
authors.lastname: Tozzi
authors.forename: Xiangcang
authors.initials: X
authors.lastname: Ye
authors.forename: Rajat
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Guang
authors.initials: G
authors.lastname: Gao
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dupre
authors.forename: Ling
authors.initials: L
authors.lastname: Xia
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Seth
authors.initials: S
authors.lastname: Bellister
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.forename: Zhang
authors.initials: Z
authors.lastname: Weihua
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D008954:Models, Biological; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D001275:ATP Citrate (pro-S)-Lyase; D051057:Proto-Oncogene Proteins c-akt; D002166:Camptothecin