title: Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation.
abstract: The Warburg effect, which reflects cancer cells' preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. The restraint on pyruvate flux into mitochondrial oxidative metabolism in cancer cells is in part attributed to the inhibition of pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential role of Src in tumor metabolism remained unclear. Here we report that activation of Src attenuated PDH activity and generation of reactive oxygen species (ROS). Conversely, Src inhibitors activated PDH and increased cellular ROS levels. Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1). Indeed, Src was the main kinase responsible for PDHA1 tyrosine phosphorylation in cancer cells. Expression of a tyrosine-289 non-phosphorable PDHA1 mutant in Src-hyperactivated cancer cells restored PDH activity, increased mitochondrial respiration and oxidative stress, decreased experimental metastasis, and sensitized cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.|School of Life Sciences, Jilin University, Changchun 130012, China.
authors: Yue
authors: Y
authors: Jin
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Qingsong
authors: Q
authors: Cai
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Anitha K
authors: AK
authors: Shenoy
authors: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors: Sangbin
authors: S
authors: Lim
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Ying
authors: Y
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Steve
authors: S
authors: Charles
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Miriam
authors: M
authors: Tarrash
authors: School of Life Sciences, Jilin University, Changchun 130012, China.
authors: Xueqi
authors: X
authors: Fu
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Sushama
authors: S
authors: Kamarajugadda
authors: Department of Surgery, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Jose G
authors: JG
authors: Trevino
authors: Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors: Ming
authors: M
authors: Tan
authors: Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors: Jianrong
authors: J
authors: Lu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D017382:Reactive Oxygen Species; D014443:Tyrosine; D019061:src-Family Kinases
keywords: Src; Warburg effect; chemoresistance; pyruvate dehydrogenase; reactive oxygen species