Targeting lactate production and efflux in prostate cancer

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Pereira-Nunes, Andreia^1,2  Simoes-Sousa, Susana^1,2,5  Pinheiro, Celine^1,2,3,4  Miranda-Goncalves, Vera^1,2,6  Granja, Sara^1,2  Baltazar, Fatima^1,2 

[1] Univ Minho, Sch Med, Life & Hlth Sci Res Inst ICVS, Campus Gualtar, P-4710057 Braga, Portugal

[2] ICVS 3Bs PT Govt Associate Lab, Braga, Guimaraes, Portugal

[3] Barretos Sch Hlth Sci Dr Paulo Prata FACISB, Barretos, SP, Brazil

[4] Barretos Canc Hosp, Mol Oncol Res Ctr, Barretos, SP, Brazil

[5] Inst Canc Res, 1237 Fulham Rd, London SW3 6JB, England

[6] Portuguese Oncol Inst Porto CI IPOP, Canc Biol & Epigenet Grp, Res Ctr, P-4200072 Porto, Portugal

关键词: Prostate cancer;    Glycolytic metabolism;    Warburg effect;    Monocarboxylate transporters (MCTs);    Lactate dehydrogenase (LDH);    Lactate;   

DOI  :  10.1016/j.bbadis.2020.165894

来源: Elsevier

【 摘 要 】

Prostate cancer (PCa) is the most commonly diagnosed cancer in men worldwide. Screening and management of PCa remain controversial and, therefore, the discovery of novel molecular biomarkers is urgently needed. Alteration in cancer cell metabolism is a recognized hallmark of cancer, whereby cancer cells exhibit high glycolytic rates with subsequent lactate production, regardless of oxygen availability. To maintain the hyperglycolytic phenotype, cancer cells efficiently export lactate through the monocarboxylate transporters MCT1 and MCT4. The impact of inhibiting lactate production/extrusion on PCa cell survival and aggressiveness was investigated in vitro and ex vivo using primary tumor and metastatic PCa cell lines and the chicken embryo chorioallantoic membrane (CAM) model. In this study, we showed the metastatic PCa cell line (DU125) displayed higher expression levels of MCT1/4 isoforms and glycolysis-related markers than the localized prostate tumor-derived cell line (22RV1), indicating these proteins are differentially expressed throughout prostate malignant transformation. Moreover, disruption of lactate export by MCT1/4 silencing resulted in a decrease in PCa cell growth and motility. To support these results, we pharmacological inhibited lactate production (via inhibition of LDH) and release (via inhibition of MCTs) and a reduction in cancer cell growth in vitro and in vivo was observed. In summary, our data provide evidence that MCT1 and MCT4 are important players in prostate neoplastic progression and that inhibition of lactate production/export can be explored as a strategy for PCa treatment.

【 授权许可】

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