Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis
Subhamoy Dasgupta, … , Arun Sreekumar, Bert W. O’Malley
Subhamoy Dasgupta, … , Arun Sreekumar, Bert W. O’Malley
Published February 9, 2015
Citation Information: J Clin Invest. 2015;125(3):1174-1188. https://doi.org/10.1172/JCI76029.
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Research Article Oncology

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 Dasgupta, Nagireddy Putluri, Weiwen Long, Bin Zhang, Jianghua Wang, Akash K. Kaushik, James M. Arnold, Salil K. Bhowmik, Erin Stashi, Christine A. Brennan, Kimal Rajapakshe, Cristian Coarfa, Nicholas Mitsiades, Michael M. Ittmann, Arul M. Chinnaiyan, Arun Sreekumar, Bert W. O’Malley

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Figure 1

SRC-2 promotes lipogenesis in prostate tumor cells primarily from glutamine sources.

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SRC-2 promotes lipogenesis in prostate tumor cells primarily from glutam...
(A) Western blot showing expression of SRC-2 and actin in C4-2 cells stably expressing shNT and 2 different clones of SRC-2 shRNA (sh18 and sh19). Actin was used to normalize protein loading. The full, uncut gels are shown in the Supplemental Material. (B) Oil Red O staining of the stable C4-2 cells shNT, sh18, and sh19 showing the neutral lipid content of the cells. Cells were counterstained with the nuclear marker DAPI, and merged images are shown in the right panels. Scale bar: 10 μm. (C) Quantitative analysis of Oil Red O staining by measuring the absorbance (OD at 490 nm) of extracted dye (n = 4). (D–G) Targeted MS–based metabolomic analyses demonstrating the relative content of palmitic, stearic, palmitoleic, and oleic acids in C4-2 cells treated with control siRNA (siGFP) or 2 different SRC-2 siRNAs (siSRC-2 #1 and siSRC-2 #2) (n = 4/group). Data are represented as the mean ± SEM. **P < 0.001 by Student’s t test versus shNT or siGFP.