Molecular and Cellular Pathobiology Caveolin-1 Increases Aerobic Glycolysis in Colorectal Cancers by Stimulating HMGA1-Mediated GLUT3 Transcription

Caveolin-1 (CAV1) acts as a growth suppressor in various humanmalignancies, but its expression is elevated in many advanced cancers, suggesting the oncogenic switch of its role during tumor progression. To understand the molecular basis for the growth-promoting function of CAV1, we characterized its expression status, differential roles for tumor growth, and effect on glucose metabolism in colorectal cancers. Abnormal elevation of CAV1 was detected in a substantial fraction of primary tumors and cell lines and tightly correlated with promoter CpG sites hypomethylation. Depletion of elevated CAV1 led to AMPK activation followed by a p53-dependent G1 cell-cycle arrest and autophagy, suggesting that elevated CAV1 may contribute to ATP generation. Furthermore, CAV1 depletion downregulated glucose uptake, lactate accumulation, and intracellular ATP level, supporting that aerobic glycolysis is enhanced by CAV1. Consistently, CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. Ectopic expression of HMGA1 increased glucose uptake, whereas its knockdown caused AMPK activation. In addition, GLUT3 expression was strongly induced by cotransfection of CAV1 and HMGA1, and its overexpression was observed predominantly in tumors harboring high levels of CAV1 and HMGA1. Together, these data show that elevated CAV1 upregulates glucose uptake and ATP production through HMGA1-mediated GLUT3 transcription, suggesting that CAV1 may render tumor cells growth advantages by enhancing aerobic glycolysis. Cancer Res; 72(16); 4097–109. 2012 AACR. Introduction Caveolin-1 (CAV1) is a structural component of caveolae and involved in diverse cellular functions such as vesicular transport, cholesterol homeostasis, and signal transduction (1). Despite a growing body of evidence on CAV1 implication in tumorigenesis, its role in cancer development and progression is still contentious. Both tumor suppression and promotion roles of CAV1 have been proposed on the basis of its expression levels detected in cancers. CAV1 expression is reduced inmany human cancers and also downregulated in cells transformed by oncogenes, such as v-Abl, Bcr-Abl, and H-Ras (1, 2). Moreover, CAV1 null mice are more susceptible to carcinogeninduced skin tumor formation, and a mutation in CAV1 has been identified in 16%of scirrhous breast carcinoma, leading to the proposal that CAV1may function as a tumor suppressor (3, 4). Nevertheless, accumulating evidence argues that CAV1 has tumor-promoting functions. CAV1 is increased in several cancers, including prostate and breast carcinomas, and its elevation is associatedwith enhanced tumor progression,multidrug resistance, and metastatic activity (5, 6). However, the molecular basis for its oncogenic effects remained largely undefined. Cancer cells often take up high amounts of glucose and rely on glycolysis rather than mitochondrial respiration for ATP generation despite the presence of oxygen, a phenomenon known as the Warburg effect (7). This metabolic shift toward aerobic glycolysis enables cancer cells to convert glucose more efficiently into macromolecules, which are needed for rapid cell growth. Glucose is a hydrophilic molecule that cannot enter the cell by simple diffusion and thus expression of specific facilitative transporters, named as GLUT is commonly elevated in cancer cells. GLUT3, one of the 14 members of the SLC2 family of GLUTs, is highly expressed in various cancer cells including colon carcinoma (8, 9). Previous studies showed that CAV1 is associated with glucose metabolism (10–12). It was also reported that insulin receptors are localized in caveolaemicrodomains and the structure of caveolae is important in glucose uptake (11). Furthermore, a recent study Authors' Affiliations: School of Life Sciences and Biotechnology, Korea University; Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul; and Department of Internal Medicine, Ilsan Paik Hospital, College of Medicine, Inje University, Goyang, Korea Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Correspondence Author: Sung-Gil Chi, School of Life Sciences and Biotechnology, Korea University, 136-701 Seoul, Republic of Korea. Phone: 82-2-3290-3443; Fax: 82-2-927-5458; E-mail: [email protected] doi: 10.1158/0008-5472.CAN-12-0448 2012 American Association for Cancer Research. Cancer Research www.aacrjournals.org 4097 on April 29, 2017. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst June 15, 2012; DOI: 10.1158/0008-5472.CAN-12-0448