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Published on: September 3, 2013
The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer
Stephen Yiu Chuen Choi1, Hui Xue1, Rebecca Wu2
1The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
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.
Insights
Targeting MCT4 (monocarboxylate transporter 4) with antisense oligonucleotides (ASOs) effectively reduced lactic acid secretion and proliferation in castration-resistant prostate cancer (CRPC) models. This approach shows promise for CRPC therapy by interfering with cancer's altered metabolism.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Castration-resistant prostate cancer (CRPC) management remains challenging.
- Current therapies targeting androgen receptor signaling are not curative.
- Cancer cells reprogram glucose metabolism (aerobic glycolysis), secreting lactic acid, which fuels tumor growth and progression.
Purpose of the Study:
- To investigate monocarboxylate transporter 4 (MCT4) as a therapeutic target in CRPC.
- To evaluate the efficacy of MCT4-targeting antisense oligonucleotides (ASOs) in preclinical CRPC models.
Main Methods:
- MCT4 protein expression was assessed in human prostate cancer tissues.
- Specific MCT4 ASOs were designed and tested in CRPC cell lines.
- Effects on MCT4 expression, lactic acid secretion, glucose consumption, and cell proliferation were measured.
- Tumor growth inhibition was evaluated in a mouse xenograft model (PC-3 tumors).
Main Results:
- Elevated MCT4 expression correlated with human CRPC and earlier relapse.
- MCT4 ASO treatment significantly reduced MCT4 expression and lactic acid secretion in CRPC cells.
- MCT4 ASOs decreased aerobic glycolysis and cell proliferation while increasing intracellular lactic acid.
- In vivo, MCT4 ASOs markedly inhibited PC-3 tumor growth with minimal host toxicity.
Conclusions:
- MCT4 is a potential therapeutic target for CRPC.
- MCT4-targeting ASOs offer a novel strategy to interfere with cancer's reprogrammed energy metabolism.
- This approach may be beneficial for treating CRPC and other cancers.
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