The MCT4 Gene: 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.

• Authors: Stephen Yiu Chuen Choi, Hui Xue, Rebecca Wu, Ladan Fazli, Dong Lin, Colin C Collins, Martin E Gleave, Peter W Gout, Yuzhuo Wang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 11 Pg. 2721-33 (06 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26755530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Monocarboxylic Acid Transporters
• Muscle Proteins
• Oligonucleotides, Antisense
• SLC16A4 protein, human
• Glucose

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Disease-Free Survival
• Gene Expression
• Gene Knockdown Techniques
• Glucose (metabolism)
• Humans
• Inhibitory Concentration 50
• Injections, Intraperitoneal
• Male
• Mice, Nude
• Monocarboxylic Acid Transporters (biosynthesis, genetics)
• Muscle Proteins (biosynthesis, genetics)
• Neoplasm Invasiveness
• Neoplasm Recurrence, Local (metabolism)
• Oligonucleotides, Antisense (administration & dosage, genetics, pharmacology)
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, mortality, therapy)
• Xenograft Model Antitumor Assays