MCT4 is induced by metastasis-enhancing pathogenic mitochondrial NADH dehydrogenase gene mutations and can be a therapeutic target

Keizo Takenaga,Miho Akimoto,Makiko Itami,Nobuko Koshikawa,Hiroki Nagase,Yasutoshi Tatsumi,Jason Lin

doi:10.1038/s41598-021-92772-1

Keizo Takenaga, Miho Akimoto + Show 5 more

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https://doi.org/10.1038/s41598-021-92772-1

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Journal: Scientific Reports	Publication Date: Jun 25, 2021
Citations: 10	License type: open-access

Affiliation: Chiba Cancer Center

Abstract

Pathogenic mitochondrial NADH dehydrogenase (ND) gene mutations enhance the invasion and metastasis of various cancer cells, and they are associated with metastasis in human non-small cell lung cancer (NSCLC). Moreover, monocarboxylate transporter 4 (MCT4) is overexpressed in solid cancers and plays a role in cancer cell proliferation and survival. Here, we report that MCT4 is exclusively expressed in mouse transmitochondrial cybrids with metastasis-enhancing pathogenic ND6 mutations. A high level of MCT4 is also detected in human NSCLC cell lines and tissues predicted to carry pathogenic ND mutations and is associated with poor prognosis in NSCLC patients. MCT4 expression in the cell lines is suppressed by N-acetyl-L-cysteine. Phosphatidylinositol-3 kinase (PI3K), AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) are involved in the regulation of MCT4 expression in the transmitochondrial cybrid cells. An MCT1/4 inhibitor effectively kills NSCLC cells with predicted pathogenic ND mutations, but an MCT1/2 inhibitor does not have the same effect. Thus, MCT4 expression is augmented by pathogenic ND mutations and could be a biomarker and a therapeutic target in pathogenic ND mutation-harbouring metastatic tumours.

Highlights

It is well known that pathogenic mutations of mitochondrial DNA are responsible for mitochondrial diseases such as Leber’s hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO)1. mtDNA mutations are implicated in carcinogenesis[2]
The results showed that neither glucose uptake nor glucose transporter 1 (Glut1) expression was associated with their respective metastatic ability (Supplementary Fig. S1)
The association between monocarboxylate transporter 4 (MCT4) expression and metastatic potential was supported by Small interfering RNA (siRNA)-mediated MCT4 knockdown experiments in P29mtB82M cells in which invadopodia formation and Matrigel invasive potential were suppressed and the expression of invasion-related genes membrane type 1-matrix metalloproteinase (MT1-MMP), MMP11, plasminogen activator urokinase receptor (Plaur) and TIMPs was changed to suppress invasiveness

Summary

Introduction

It is well known that pathogenic mutations of mitochondrial DNA (mtDNA) are responsible for mitochondrial diseases such as Leber’s hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO)1. mtDNA mutations are implicated in carcinogenesis[2]. Cancer cells with malfunctioning mitochondria caused by either pathogenic mtDNA mutations or nDNA-coded respiratory chain subunit gene mutations exhibit enhanced glycolysis, resulting in the production of energy and a larger amount of lactate than what is observed in cells with normal mitochondria[20]. Intracellular lactate that is produced has to be exported out of cancer cells to prevent them from intracellular acidification and cell death To this end, MCTs play important roles, and MCT1 and MCT4 have been shown to be overexpressed in a number of cancers, including glioblastoma, colon cancer, breast cancer, prostate cancer, clear cell renal cell carcinoma, oesophageal squamous carcinoma pancreatic cancer and non-small cell lung carcinoma (NSCLC)[13,14,15,22]. MCTs are thought to be potential therapeutic t argets[30,35,36,37]

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