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

ABSTRACT

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 in silico findings were confirmed via in vitro 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.

KEYWORDS:

• Monocarboxylate transporters (MCTs)
• SLC16A family
• ovarian cancer
• lactate
• differential expression analysis
• TCGA (the cancer Genome Atlas)

Abbreviations

TCGA (The Cancer Genome Atlas), MCT (Monocarboxylate Transporter), OSC (Ovarian Serous Cystadenocarcinoma), OC (Ovarian Cancer), EOC (Epithelial Ovarian Cancer), α-CHCA (α-Cyano Hydroxy Cinnamic Acid), GTEx (Genotype-Tissue Expression), GO (Gene Ontology), KEGG (Kyoto Encyclopedia of Genes and Genomes), EMT (Epithelial to Mesenchymal Transition).

Acknowledgments

We acknowledge the extensive help from Mr Prabir Kumar Dey and all the lab members of SSR lab. We also appreciate the sincere efforts of Mr Sounak Bhattacharya for the technical assistance he provided during taking images by Confocal Microscope and Abhishake Lahiri (SRF) for valuable input and suggestions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contribution

PC, DB, and SSR conceptualized and designed the study and drafted the manuscript. PC performed the in silico and in vitro experiments and analyses. DB performed and critically reviewed the in silico studies.

Data availability statement

The data presented in this study are included in the article or supplementary information. All the raw files are available on request to the corresponding author. Data extracted from publicly available databases and web tools could be reproduced online.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19336950.2023.2273008.

Additional information

Funding

The entire work has been funded by the Council of Scientific and Industrial Research (CSIR) In-House Project (MLP-SSR/443) and CSIR Funded Mission Mode Project (HCP‐40). PC received her fellowship from CSIR, award no. 31/002(1053)/2016-EMR-I. DB would like to acknowledge the Indian Council of Medical Research (ICMR) for providing the fellowship.