Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer

Abstract

Development of neuroendocrine prostate cancer (NEPC) is emerging as a major problem in clinical management of advanced prostate cancer (PCa). As increasingly potent androgen receptor (AR)‐targeting antiandrogens are more widely used, PCa transdifferentiation into AR‐independent NEPC as a mechanism of treatment resistance becomes more common and precarious, since NEPC is a lethal PCa subtype urgently requiring effective therapy. Reprogrammed glucose metabolism of cancers, that is elevated aerobic glycolysis involving increased lactic acid production/secretion, plays a key role in multiple cancer‐promoting processes and has been implicated in therapeutics development. Here, we examined NEPC glucose metabolism using our unique panel of patient‐derived xenograft PCa models and patient tumors. By calculating metabolic pathway scores using gene expression data, we found that elevated glycolysis coupled to increased lactic acid production/secretion is an important metabolic feature of NEPC. Specific inhibition of expression of MCT4 (a plasma membrane lactic acid transporter) by antisense oligonucleotides led to reduced lactic acid secretion as well as reduced glucose metabolism and NEPC cell proliferation. Taken together, our results indicate that elevated glycolysis coupled to excessive MCT4‐mediated lactic acid secretion is clinically relevant and functionally important to NEPC. Inhibition of MCT4 expression appears to be a promising therapeutic strategy for NEPC.

MCT4 promotes cell proliferation and invasion of castration-resistant prostate cancer PC-3 cell line

“…It has been reported that MCT4 is upregulated in PCa, and that elevated expression of MCT4 protein in PCa is associated with the development of CRPC (Choi et al, 2016[ 4 ], 2018[ 5 ]). In this study, human CRPC PC-3 cell line was used as these cells present a distinct glycolytic metabolic profile, a property associated with MCT4 expression (Vaz et al, 2012[ 25 ]).…”

“…MCT4 can function as a lactate exporter or importer, and lactate could accumulate while MCT4 inhibition (Todenhofer et al, 2018[ 23 ]). The increase in MCT4 expression is associated with clinical manifestations and may play an important role in the progression of the disease to the late stage or the enhancement of cancer cell invasion (Choi et al, 2016[ 4 ], 2018[ 5 ]; Hao et al, 2010[ 15 ]; Pertega-Gomes et al, 2011[ 18 ]).…”

“…MCT4 is upregulated in tumor and has been shown to be related with poor prognosis in patients with multiple types of cancer (Chen et al, 2018[ 3 ]; Choi et al, 2018[ 5 ]; Fisel et al, 2013[ 10 ]; Todenhofer et al, 2018[ 23 ]), including PCa (Choi et al, 2016[ 4 ]; Pertega-Gomes et al, 2011[ 18 ]). In addition, upregulated MCT4 expression may be an important factor in cancer-stroma interactions facilitating PCa progression (Sanita et al, 2014[ 21 ]).…”

The epigenetic and transcriptional landscape of neuroendocrine prostate cancer

“…Moreover, MYCN, which is implicated in neuroendocrine lineage reprogramming, increases mitochondrial export of acetyl groups and upregulates the HAT GCN5 leading to elevated histone acetylation and DNA accessibility (Knoepfler et al 2006). This may explain why NEPC tumours are highly glycolytic, and inhibition of glucose metabolism leads to reduced proliferation and reversion of resistance phenotypes (Li et al 2016, Choi et al 2018.…”

Dynamics of Cellular Plasticity in Prostate Cancer Progression

“…It has also been observed that PCa switch to aerobic glycolysis only at the advanced stages of the disease progression and correlates with poor clinical outcomes (Pertega-Gomes et al, 2015 ). Of interest, the gene expression profile of NEPC patients showed glycolysis and lactic acid production as the most significantly upregulated pathways in these tumors (Choi et al, 2018 ). It has been shown that higher expression of the plasma membrane transporter monocarboxylate transporter 4 (MCT4) facilitated the enhanced secretion of lactic acid, while antisense oligonucleotides mediated silencing of MCT4 led to reduced lactic acid secretion, glucose metabolism and NEPC cell proliferation (Choi et al, 2018 ).…”