title: Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis.
abstract: Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevated in a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in 37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductive carboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesis and reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 via mTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses by coactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling of human prostate tumors identified a massive increase in the SRC-2-driven metabolic signature in metastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominent metabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severely attenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest that the SRC-2 pathway has potential as a therapeutic target for prostate cancer.
authors: Subhamoy
authors: S
authors: Dasgupta
authors: Nagireddy
authors: N
authors: Putluri
authors: Weiwen
authors: W
authors: Long
authors: Bin
authors: B
authors: Zhang
authors: Jianghua
authors: J
authors: Wang
authors: Akash K
authors: AK
authors: Kaushik
authors: James M
authors: JM
authors: Arnold
authors: Salil K
authors: SK
authors: Bhowmik
authors: Erin
authors: E
authors: Stashi
authors: Christine A
authors: CA
authors: Brennan
authors: Kimal
authors: K
authors: Rajapakshe
authors: Cristian
authors: C
authors: Coarfa
authors: Nicholas
authors: N
authors: Mitsiades
authors: Michael M
authors: MM
authors: Ittmann
authors: Arul M
authors: AM
authors: Chinnaiyan
authors: Arun
authors: A
authors: Sreekumar
authors: Bert W
authors: BW
authors: O'Malley
mesh_terms: D000818:Animals; D002470:Cell Survival; D004734:Energy Metabolism; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D050155:Lipogenesis; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D051958:Nuclear Receptor Coactivator 2 / Q000502:physiology*; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D005973:Glutamine