Prostate Cancer Proliferation Is Affected by the Subcellular Localization of MCT2 and Accompanied by Significant Peroxisomal Alterations.

Isabel Valença,Sandra Kühl,Daniela Ribeiro,Ana Rita Ferreira,Marcelo Correia,Carlo Van Roermund,Valdemar Máximo,Hans R Waterham,Markus Islinger

doi:10.3390/cancers12113152

Abstract

Simple SummaryFatty acid β-oxidation is a dominant bioenergetic pathway in prostate cancer. It has recently been suggested that the specific targeting of monocarboxylate transporter 2 (MCT2) to peroxisomes contributed to an increase in β-oxidation rates and maintenance of the redox balance in prostate cancer cells. Here we provide evidence demonstrating that prostate cancer streamlines peroxisome metabolism by upregulating distinct pathways involved in lipid metabolism. Importantly, we show that the localization of MCT2 at peroxisomes is required for prostate cancer cell proliferation. Our results emphasize the importance of peroxisomes for prostate cancer development and highlight different cellular mechanisms that may be further explored as possible targets for prostate cancer therapy.Reprogramming of lipid metabolism directly contributes to malignant transformation and progression. The increased uptake of circulating lipids, the transfer of fatty acids from stromal adipocytes to cancer cells, the de novo fatty acid synthesis, and the fatty acid oxidation support the central role of lipids in many cancers, including prostate cancer (PCa). Fatty acid β-oxidation is the dominant bioenergetic pathway in PCa and recent evidence suggests that PCa takes advantage of the peroxisome transport machinery to target monocarboxylate transporter 2 (MCT2) to peroxisomes in order to increase β-oxidation rates and maintain the redox balance. Here we show evidence suggesting that PCa streamlines peroxisome metabolism by upregulating distinct pathways involved in lipid metabolism. Moreover, we show that MCT2 is required for PCa cell proliferation and, importantly, that its specific localization at the peroxisomal membranes is essential for this role. Our results highlight the importance of peroxisomes in PCa development and uncover different cellular mechanisms that may be further explored as possible targets for PCa therapy.

Highlights

Malignant transformation requires multiple metabolic adaptations to respond to energy requirements and to support high cell proliferation rates [1]
We have previously reported that the monocarboxylate transporter 2 (MCT2), usually associated with glucose metabolism and overexpressed in cancer [19,20], localizes mainly to peroxisomes in prostate cancer (PCa) cells derived from localized tumors [18]
In order to further identify peroxisome-dependent pathways that may be involved in PCa malignant transformation and progression, we analyzed the expression of a set of peroxisomal proteins in different cellular models representing distinct stages of PCa disease progression: PNT1A cells, 22Rv1 cells, and PC3 cells (Figure 1 and Figure S1)

Summary

Introduction

Malignant transformation requires multiple metabolic adaptations to respond to energy requirements and to support high cell proliferation rates [1]. Some cancers take advantage from fatty acid oxidation for energy production [4,7]. Prostate cancer (PCa) has an exclusive metabolic profile: PCa cells exhibit lower glucose consumption rates than most tumor cells and lipids become the main energy source [8]. The central role of lipids in PCa malignancy is supported by the increased uptake of circulating lipids, transfer of fatty acids from stromal adipocytes to PCa cells, and the de novo fatty acid synthesis and fatty acid oxidation [9,10,11]. PCa is conditioned by the response to androgens, which significantly modulate de novo fatty acid synthesis [12]

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