Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways

Abstract

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into two main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery, and radiotherapy. The 5-year survival rate has plateaued at 70% since 2000, despite several clinical trials. RMS cells are thought to derive from the muscle lineage. During development, myogenesis includes the expansion of muscle precursors, the elimination of those in excess by cell death and the differentiation of the remaining ones into myofibers. The notion that these processes may be hijacked by tumor cells to sustain their oncogenic transformation has emerged, with RMS being considered as the dark side of myogenesis. Thus, dissecting myogenic developmental programs could improve our understanding of RMS molecular etiology. We focused herein on ANT1, which is involved in myogenesis and is responsible for genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a dual functionality, as it is involved both in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore. Bioinformatics analyses of transcriptomic datasets revealed that ANT1 is expressed at low levels in RMS. Using the CRISPR-Cas9 technology, we showed that reduced ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects arise notably from an abnormal metabolic switch induced by ANT1 downregulation. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapy. Based on our results, modulation of ANT1 expression and/or activity appears as an appealing therapeutic approach in RMS management.

Mitochondrial calcium uptake regulates tumour progression in embryonal rhabdomyosarcoma

“…Previous studies have suggested deregulation of oxidative stress in ERMS [ 10 , 29 , 30 ]. We therefore examined mitochondrial Ca 2+ uptake, oxygen consumption rate (OCR) and adenosine triphosphate (ATP)-linked respiration in three patient-derived ERMS cell lines (RD, RD18 and JR1).…”

Comprehensive Analysis and Validation of Solute Carrier Family 25 (SLC25) in Pan-Cancer

“…We found that SLC25A4 and SLC25A23 were respectively decreased in gastric cancer and colon cancer, while SLC25A7 was increased in gastric cancer, which was consistent with our bioinformatic prediction. It has been shown that the ANT1 protein encoded by SLC25A4 was low expressed in rhabdomyosarcoma [7]. Combining with this, SLC25A4 is located in mitochondria and involved in metabolic process by regulating ATP/ADP.…”

Comprehensive Analysis and Validation of Solute Carrier Family 25 (SLC25) and Its Correlation with Immune Infiltration in Pan-Cancer

“…This may be related to the few samples or the existence of posttranscriptional regulation. It has been shown that the ANT1 protein encoded by SLC25A4 was also lowly expressed in rhabdomyosarcoma [ 13 ]. Combining with this, ANT1 transports ADP to mitochondrial matrix and synthesizes ATP there, then exports it to the cytoplasm to provide fuel for the metabolic energy process [ 14 ].…”