Mitochondrial Impairment by MitoBloCK-6 Inhibits Liver Cancer Cell Proliferation.

Fernanda Borges,Tiago Barros Silva,Anna Fuhrmann,Stefanie M. Hauck,Percy Knolle,Anna Becker,Bernhard Michalke,Yaschar Kabiri,Hans Zischka,Luisa Jedermann,Carola Eberhagen,Ann-Christine König

doi:10.3389/fcell.2021.725474

Abstract

Augmenter of liver regeneration (ALR) is a critical multi-isoform protein with its longer isoform, located in the mitochondrial intermembrane space, being part of the mitochondrial disulfide relay system (DRS). Upregulation of ALR was observed in multiple forms of cancer, among them hepatocellular carcinoma (HCC). To shed light into ALR function in HCC, we used MitoBloCK-6 to pharmacologically inhibit ALR, resulting in profound mitochondrial impairment and cancer cell proliferation deficits. These effects were mostly reversed by supplementation with bioavailable hemin b, linking ALR function to mitochondrial iron homeostasis. Since many tumor cells are known for their increased iron demand and since increased iron levels in cancer are associated with poor clinical outcome, these results help to further advance the intricate relation between iron and mitochondrial homeostasis in liver cancer.

Highlights

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancers
As MB-6 interferes with yeast as well as human cancer mitochondria (Dabir et al, 2013; Singh et al, 2020), this approach offers a reasonable extent of specific subcellular compound activity and a most plausible action on the mitochondrial Augmenter of liver regeneration (ALR) isoform
The mitochondrial disulfide relay system (DRS) is an essential part of protein maturation in eukaryotic cells, highlighted by the finding that mutations in the ALR gene are associated with mitochondrial myopathies and impairment of the respiratory chain (Di Fonzo et al, 2009; Nambot et al, 2017)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancers. It represents the fourth most common cause of cancer-related deaths worldwide (Kim and Viatour, 2020). Hepatitis B and C are regarded as the leading cause of HCC, the sharp rise in non-alcoholic fatty liver disease (NAFLD) as well as alcoholic and non-alcoholic steatohepatitis (ASH/NASH) are becoming strong contributing factors for the remarkable increase in HCC incidence in Western Countries (Anstee et al, 2019). This, combined with the often underlying liver cirrhosis, strongly limits treatment options and mostly rules out curative approaches (Llovet et al, 2008). HCC is notoriously resistant to chemical and radiation treatments.

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