GLUT12 promotes prostate cancer cell growth and is regulated by androgens and CaMKK2 signaling

Abstract

Despite altered metabolism being an accepted hallmark of cancer, it is still not completely understood which signaling pathways regulate these processes. Given the central role of androgen receptor (AR) signaling in prostate cancer, we hypothesized that AR could promote prostate cancer cell growth in part through increasing glucose uptake via the expression of distinct glucose transporters. Here, we determined that AR directly increased the expression of , the gene that encodes the glucose transporter GLUT12. In support of these findings, gene signatures of AR activity correlated with expression in multiple clinical cohorts. Functionally, GLUT12 was required for maximal androgen-mediated glucose uptake and cell growth in LNCaP and VCaP cells. Knockdown of GLUT12 also decreased the growth of C4-2, 22Rv1 and AR-negative PC-3 cells. This latter observation corresponded with a significant reduction in glucose uptake, indicating that additional signaling mechanisms could augment GLUT12 function in an AR-independent manner. Interestingly, GLUT12 trafficking to the plasma membrane was modulated by calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-5'-AMP-activated protein kinase (AMPK) signaling, a pathway we previously demonstrated to be a downstream effector of AR. Inhibition of CaMKK2-AMPK signaling decreased GLUT12 translocation to the plasma membrane by inhibiting the phosphorylation of TBC1D4, a known regulator of glucose transport. Further, AR increased expression. Correspondingly, expression of correlated with AR activity in prostate cancer patient samples. Taken together, these data demonstrate that prostate cancer cells can increase the functional levels of GLUT12 through multiple mechanisms to promote glucose uptake and subsequent cell growth.

Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease

“…TBC1D4 may not be exclusively involved in GLUT4 vesicle traffic as it has been recently shown to participate in the cell surface expression of GLUT12 in response to activation of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and AMPK signaling [253]. Likewise, overexpression of phospho-site mutants of TBC1D1 and TBC1D4 was reported to reduce cell surface expression of GLUT1 in non-insulin target cells [90].…”

Structure, function and regulation of mammalian glucose transporters of the SLC2 family

“…It is important in foetal development, particularly of the heart, while GLUT12 deficiency is associated with heart failure [ 105 ]. GLUT12 expression is upregulated by androgens in the prostate and levels are increased in prostate cancers [ 10 , 39 , 224 ].…”

Regulation of SLC1A4 and SLC1A5 in Prostate Cancer—Response

“…We also wish to acknowledge prior work from Wang and colleagues that demonstrated that androgens could increase the expression of SLC1A4 and SLC1A5 in LNCaP cells and their expression was increased in prostate cancer patient samples (7,8). It is true that similar data for SLC1A5 (alongside our mined SLC1A4 clinical data) were presented in Dr. Holst's 2015 study (7), but it was unintentional as evidenced from our published work on unrelated topics (9) including work done by us well before any of these studies (10), demonstrating that this is a common format we use to present these types of clinical data. Importantly, while our study further validates the work of Wang and colleagues that defined the functional importance of SLC1A5/ASCT2 in prostate cancer (7,8), there were some important differences.…”