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 8

SRC-2 is essential for prostate cancer cell survival.

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SRC-2 is essential for prostate cancer cell survival. (A) Representative...
(A) Representative images depicting the growth of the stable C4-2 cells shNT, sh18, and sh19 in soft agar assay 2 weeks after plating. (B) Quantification of the total number of stable C4-2 cell colonies that survived after 2 weeks. *P <0.05 by 1-way ANOVA. (C) H&E-stained sections of mouse lungs from experimental lung metastasis assay. Nude mice were injected via the tail vein with PC-3 cells stably expressing shNT, sh18, and sh19 (n = 7), and growth and survival of the cells in mouse lungs were analyzed after 5 weeks. T, tumor. Scale bar: 100 μm. (D) Quantification of Ki67-stained cells (antibody epitope reacts with human Ki67 protein) in mouse lung sections from shNT-, sh18-, and sh19-injected animals. *P < 0.05 and **P < 0.001 by 2-tailed Student’s t test. Refer also to Supplemental Figure 11C. (E) Western blot analysis showing expression levels of SRC-2, FASN, SCD, and actin in the stable C4-2 cells shNT and sh19, and reexpression of SRC-2 in sh19 cells infected with SRC-2 adenovirus. Actin was normalized to the protein loading control. The full, uncut gels are shown in the Supplemental Material. (F) Clonogenic survival assay in the stable PC-3 cells shNT, sh18, and sh19 expressing GFP adenovirus, SRC-2 adenovirus, or FASN adenovirus to rescue the defective survival phenotype in SRC-2–depleted cells. (G) Relative growth of C4-2 and PC-3 cells stably expressing shNT that were either untreated or treated with DMSO or BPTES (1 μM) for 4 days. sh19 cells were used to monitor the effect of SRC-2 knockdown (n = 6/group). Data represent the mean ± SEM. *P < 0.05 compared with DMSO and **P < 0.001 by 2-way ANOVA with Tukey’s multiple comparisons test.