ATP citrate lyase mediates resistance of colorectal cancer cells to SN38

Yunfei Zhou, Lakshmi Reddy Bollu, Federico Tozzi, Xiangcang Ye, Rajat Bhattacharya, Guang Gao, Elizabeth Dupre, Ling Xia, Jia Lu, Fan Fan, Seth Bellister, Lee M. Ellis, Zhang Weihua

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 ofAKTsignaling andACLy 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.

Original languageEnglish (US)
Pages (from-to)2782-2791
Number of pages10
JournalMolecular Cancer Therapeutics
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

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ATP Citrate (pro-S)-Lyase
Colorectal Neoplasms
irinotecan
oxaliplatin
Drug Resistance
Lentivirus
Lipogenesis
Therapeutic Uses
Combination Drug Therapy
Fluorouracil
Proteomics
Small Interfering RNA
Neoplasms
Mucous Membrane

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhou, Y., Bollu, L. R., Tozzi, F., Ye, X., Bhattacharya, R., Gao, G., ... Weihua, Z. (2013). ATP citrate lyase mediates resistance of colorectal cancer cells to SN38. Molecular Cancer Therapeutics, 12(12), 2782-2791. https://doi.org/10.1158/1535-7163.MCT-13-0098

ATP citrate lyase mediates resistance of colorectal cancer cells to SN38. / Zhou, Yunfei; Bollu, Lakshmi Reddy; Tozzi, Federico; Ye, Xiangcang; Bhattacharya, Rajat; Gao, Guang; Dupre, Elizabeth; Xia, Ling; Lu, Jia; Fan, Fan; Bellister, Seth; Ellis, Lee M.; Weihua, Zhang.

In: Molecular Cancer Therapeutics, Vol. 12, No. 12, 01.12.2013, p. 2782-2791.

Research output: Contribution to journalArticle

Zhou, Y, Bollu, LR, Tozzi, F, Ye, X, Bhattacharya, R, Gao, G, Dupre, E, Xia, L, Lu, J, Fan, F, Bellister, S, Ellis, LM & Weihua, Z 2013, 'ATP citrate lyase mediates resistance of colorectal cancer cells to SN38', Molecular Cancer Therapeutics, vol. 12, no. 12, pp. 2782-2791. https://doi.org/10.1158/1535-7163.MCT-13-0098
Zhou, Yunfei ; Bollu, Lakshmi Reddy ; Tozzi, Federico ; Ye, Xiangcang ; Bhattacharya, Rajat ; Gao, Guang ; Dupre, Elizabeth ; Xia, Ling ; Lu, Jia ; Fan, Fan ; Bellister, Seth ; Ellis, Lee M. ; Weihua, Zhang. / ATP citrate lyase mediates resistance of colorectal cancer cells to SN38. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 12. pp. 2782-2791.
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