期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1864, 期 3, 页码 413-421出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2018.06.005
关键词
In-cell metabolomics; ACSS2; Acetate; Cisplatin resistance; Bladder cancer
资金
- National Institutes of Health [1U01DK103260]
- Department of Defense [W81XWH-15-1-0415]
- Centers for Disease Control and Prevention [1U01DP006079]
- Steven Spielberg Discovery Fund in Prostate Cancer Research Career Development Award
- Burroughs Wellcome Fund (BWF) 2017 Collaborative Research Travel Grant (CRTG)
- Southeast Center for Integrated Metabolomics (SECIM) Pilot and Feasibility Grant
- U.S. - Egypt Science and Technology (ST) Joint Fund
- National Academies of Sciences, Engineering, and Medicine
- USAID
- Basic Science Research Program through the National Research Foundation of Korea - Ministry of Education, Science, and Technology [2014-069340, NRF-2018R1A3B1052328]
- Bio-Synergy Research Project [NRF-2015M3A9C4075818]
- National Key R&D Program of China [2017YFA0503900]
- Natural Science Foundation of China [31701099]
- Science and Technology Foundation of Shenzhen City [JCYJ20170302144650949, JCYJ20170818094707964]
- Natural Science Foundation of Guangdong Province [2017A030310459]
- Natural Science Foundation of SZU [2017085]
Cisplatin is an important chemotherapeutic agent against metastatic bladder cancer, but resistance often limits its usage. With the recent recognition of lipid metabolic alterations in bladder cancers, we studied the metabolic implications of cisplatin resistance using cisplatin-sensitive (T24S) and resistant (T24R) bladder cancer cells. Real-time live metabolomics revealed that T24R cells consume more glucose, leading to higher production of glucose-derived acetate and fatty acids. Along with the activation of general metabolic regulators, enzymes involved in acetate usage (ACSS2) and fatty acid synthesis (ACC) and a precursor for fatty acid synthesis (acetylCoA) were elevated in T24R cells. Consistently, metabolic analysis with C-13 isotope revealed that T24R cells preferred glucose to acetate as the exogenous carbon source for the increased fatty acid synthesis, contrary to T24S cells. In addition, ACSS2, rather than the well-established ACLY, was the key enzyme that supplies acetylCoA in T24R cells through glucose-derived endogenous acetate. The relevance of ACSS2 in cisplatin resistance was further confirmed by the abrogation of resistance by an ACSS2 inhibitor and, finally, by the higher expression of ACSS2 in the patient tissues with cisplatin resistance. Our results may help improve the treatment options for chemoresistant bladder cancer patients and provide possible vulnerability targets to overcome the resistance.
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