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.
View: Text | PDF
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

×

Figure 4

SRC-2 represses transcription of the zinc transporter ZIP1 to stimulate ACO activity.

Options: View larger image (or click on image) Download as PowerPoint
SRC-2 represses transcription of the zinc transporter ZIP1 to stimulate ...
(A–C) Enzymatic activity of ACO, IDH, and CS in the stable C4-2 cells shNT, sh18, and sh19 (n = 5). (D) qRT-PCR analysis of SRC2 and ZIP1 (SLC39A1) gene expression in the stable C4-2 cells shNT and sh18 and in C4-2 shNT cells expressing SRC-2 adenovirus (n = 4/group). *P < 0.05 by 2-way ANOVA with Tukey’s multiple comparisons test. (E) ChIP of SRC-2 from C4-2 cells showing the recruitment of SRC-2 on the ZIP1 proximal promoter (–175 to 70 bp) compared with the –5,000 bp upstream region from the start site. (F) Luciferase reporter assay in HeLa cells transiently transfected with empty pGL3 vector (Empty luciferase) and a pGL3-ZIP1-luciferase construct (–246 to +82 bp) in the presence of vector alone (ZIP1 luciferase) or of the SRC-2 construct (ZIP1-luc + SRC-2) (n = 6). (G) Mass isotopomer distribution of stearate labeling from [5-13C]glutamine in C4-2 cells ectopically expressing human ZIP1 (Adv ZIP1) or control virus (Adv GFP) (n = 3). The mass spectrometric method used in this study failed to detect higher fatty acid isotopomers. Data represent the mean ± SEM. *P < 0.05 and **P < 0.001 by Student’s t test (A, E, and F), with Holm-Sidak multiple comparisons test in G.