TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

Abstract

Purpose: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling–directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer. Experimental Design: A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice. Results: Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity. Conclusions: MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721–33. ©2016 AACR.

Metabolic heterogeneity signature of primary treatment-naïve prostate cancer

“…Reprogramming energy metabolism is an important hallmark of cancer [3, 4] and abnormal metabolic characteristics of cancers have been implicated as potential diagnostic/prognostic biomarkers [5–9]. Thus in contrast to normal resting cells whose energy production is mainly based on mitochondrial oxidative phosphorylation, the majority of cancer cells rely on aerobic glycolysis coupled to increased glucose uptake and lactic acid production/secretion (the Warburg effect) [3, 7].…”

“…The augmented glucose consumption can be observed using ( 18 F)-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) [10, 11]. However, prostate cancers are characterized by a lack of increased glycolysis rendering FDG-PET less effective in imaging this malignancy [12], (although a small group of tumours do utilize aerobic glycolysis [9]). Instead, prostate cancers have abnormal metabolisms for citrate and choline [13–15] and are characterized by increased levels of choline-containing compounds (ChoCCs).…”

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

“…Thus, as shown in Figure 2, in vitro incubation of LNCaP cells with Aneustat led to substantial decreases in glucose consumption (∼82%), lactic acid secretion (∼56%) and downregulation of expression of major glycolysis‐related genes, i.e. GLUT1 (encoding the glucose transporter), LDHA (encoding lactate dehydrogenase A) and MCT4 (encoding a major plasma membrane transporter of cancer‐generated lactic acid8). The finding that Aneustat led to upregulation of genes of the glutaminolysis pathway (Supporting Information Fig.…”

“…LNCaP cells were treated with vehicle control and Aneustat for 48 hr; whole cell protein extracts were resolved on SDS‐PAGE using procedures previously reported 8. Proteins were then transferred to PVDF membranes.…”

“…Thus a reduction of lactic acid secretion by the tumors, obtained by specific depletion of lactate dehydrogenase‐A (LDHA), led to lower numbers of intratumoral MDSCs and higher numbers of intratumoral NK cells and CD8 + T cells compared to controls 10. As such, targeting aerobic glycolysis to reduce lactic acid secretion by cancer cells appears to be a useful strategy for restoring the host anticancer immune response 7, 8. This would lead to a higher ratio of CD8 + T cells to Treg cells, a higher number of NK cells and a lower number of MDSCs – a signature associated with improved patient outcome 12, 13, 14, 15…”