A systemic analysis of monocarboxylate transporters in ovarian cancer and possible therapeutic interventions

Monocarboxylate transporters (MCTs) play an immense role in metabolically active solid tumors by regulating concentration-dependent transport of different important monocarboxylates including pyruvate and lactate and are encoded by the SLC16A family of genes. Given the vast array of functions, these transporters play in oncogenesis, our objective was to look into the association of MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8), and MCT4 (SLC16A3) with Epithelial ovarian cancer (EOC) pathophysiology by exploiting various publicly available databases and web resources. Few of the <i>in silico</i> findings were confirmed via <i>in vitro</i> experiments in EOC cell lines, SKOV3 and OAW-42. MCT1 and MCT4 were found to be upregulated at the mRNA level in OC tissues compared to normal. However, only higher level of MCT4 mRNA was found to be associated with poor patient survival. MCT4 was positively correlated with gene families responsible for invasion, migration, and immune modification, proving it to be one of the most important MCTs for therapeutic intervention. We compared the effects of MCT1/2 blocker SR13800 and a broad-spectrum MCT blocker α-Cyano Hydroxy Cinnamic Acid (α-CHCA) and discovered that α-CHCA has a greater effect on diminishing the invasive behavior of the cancer cells than MCT1/2 blocker SR13800. From our study, MCT4 has emerged as a prospective marker for predicting poor patient outcomes and a potential therapeutic target.

单羧酸转运蛋白（Monocarboxylate Transporters, MCTs）通过调控包括丙酮酸、乳酸在内的多种重要单羧酸的浓度依赖性转运过程，在代谢活跃的实体瘤中发挥关键作用，其编码基因为SLC16A基因家族。鉴于此类转运蛋白在肿瘤发生过程中参与的功能极为多样，本研究旨在借助各类公开数据库与网络资源，探究MCT1（SLC16A1）、MCT2（SLC16A7）、MCT3（SLC16A8）及MCT4（SLC16A3）与上皮性卵巢癌（Epithelial Ovarian Cancer, EOC）病理生理学的关联。部分计算机模拟（in silico）实验结果通过体外（in vitro）实验，在EOC细胞系SKOV3与OAW-42中得到验证。相较于正常卵巢组织，卵巢癌组织中MCT1与MCT4的mRNA水平显著上调。然而，仅MCT4的高mRNA表达与患者不良生存预后相关。MCT4与参与肿瘤侵袭、迁移及免疫修饰的基因家族呈正相关，证实其为极具临床转化价值的治疗干预靶点之一。本研究对比了MCT1/2抑制剂SR13800与广谱MCT抑制剂α-氰基羟基肉桂酸（α-Cyano Hydroxy Cinnamic Acid, α-CHCA）的作用效果，发现α-CHCA相较MCT1/2抑制剂SR13800，对癌细胞侵袭行为的抑制效果更为显著。本研究结果表明，MCT4可作为预测患者不良预后的潜在生物标志物，同时也是极具潜力的治疗靶点。