Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis
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
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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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 2

SRC-2 promotes lipogenesis by reductive glutamine metabolism.

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SRC-2 promotes lipogenesis by reductive glutamine metabolism. (A) Mass i...
(A) Mass isotopomer distribution of citrate extracted from the stable C4-2 cells shNT (nontargeting) and SRC-2 shRNA clones sh18 and sh19 cultured in the presence of 2 mM L-[U-13C]glutamine and 11 mM unlabeled glucose for 24 hours (n = 6). *P < 0.05 and **P < 0.001 by 2-way ANOVA with Tukey’s multiple comparisons test. (B and C) Citrate and α-ketoglutarate (α-KG) labeling from [1-13C]glutamine ([1-13C]gln) in the stable C4-2 cells shNT and sh19 (n = 3). (D) Mass isotopomer distribution of stearate labeling from [5-13C]glutamine ([5-13C]gln) in the stable C4-2 cells shNT and sh19 (n = 3). The mass spectrometric method used in this study failed to detect higher fatty acid isotopomers. *P < 0.05 by Student’s t test with Holm-Sidak multiple comparisons test. (E) qRT-PCR analysis of FASN, SCD, and SRC2 gene expression in the stable C4-2 cells shNT, sh18, and sh19 (n = 4). Relative mRNA expression was normalized to actin (housekeeping gene). (F) qRT-PCR analysis of FASN, SCD, and SRC2 gene expression in C4-2 cells expressing GFP (Adv GFP) and SRC-2 (Adv SRC-2) adenovirus (n = 3). Relative mRNA expression was normalized to actin (housekeeping gene). (G) Western blot analysis of FASN, SCD, and SRC-2 in the stable C4-2 cells shNT, sh18, and sh19 and in C4-2 cells expressing GFP adenovirus or SRC-2 adenovirus (n = 3). Actin was used to normalize protein loading. The full, uncut gels are shown in the Supplemental Material. Data are represented as the mean ± SEM. *P < 0.05 and **P < 0.001 by Student’s t test (B–F).