Loss of SLC25A11 causes suppression of NSCLC and melanoma tumor formation

Abstract

BackgroundFast growing cancer cells require greater amounts of ATP than normal cells. Although glycolysis was suggested as a source of anabolic metabolism based on lactate production, the main source of ATP to support cancer cell metabolism remains unidentified.MethodsWe have proposed that the oxoglutarate carrier SLC25A11 is important for ATP production in cancer by NADH transportation from the cytosol to mitochondria as a malate. We have examined not only changes of ATP and NADH but also changes of metabolites after SLC25A11 knock down in cancer cells.FindingsThe mitochondrial electron transport chain was functionally active in cancer cells. The cytosolic to mitochondrial NADH ratio was higher in non-small cell lung cancer (NSCLC) and melanoma cells than in normal cells. This was consistent with higher levels of the oxoglutarate carrier SLC25A11. Blocking malate transport by knockdown of SLC25A11 significantly impaired ATP production and inhibited the growth of cancer cells, which was not observed in normal cells. In in vivo experiments, heterozygote of SLC25A11 knock out mice suppressed KRASLA2 lung tumor formation by cross breeding.InterpretationCancer cells critically depended on the oxoglutarate carrier SLC25A11 for transporting NADH from cytosol to mitochondria as a malate form for the purpose of ATP production. Therefore blocking SLC25A11 may have an advantage in stopping cancer growth by reducing ATP production.FundThe Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT to SYK (NRF-2017R1A2B2003428).

ATP Production Relies on Fatty Acid Oxidation Rather than Glycolysis in Pancreatic Ductal Adenocarcinoma

“…This markedly lowered ATP production and inhibited the growth of cancer cells, which was not observed in normal cells. [22]. These findings suggest that MAS is a major contributor to ATP production in cancer.…”

“…We found that cancer cells prefer to use cytosolic NADH as an electron donor for ATP production through electron transfer complex [12][13][14][19][20][21][22]. To block the transfer of cytosolic NADH into mitochondria, we knocked down SLC25A11, the mitochondrial 2-oxoglutarate/malate carrier protein in the malate aspartate shuttle (MAS).…”

Mucosal Melanoma of the Head and Neck: From Diagnosis to Treatment

“…Mucosal melanoma of the head and neck (HNMM) region constitutes 55% of all mucosal melanomas, but <10% of all melanomas of the head and neck region. A majority of these tumors are found in the sinonasal regions (55%), while the rest are located in the oral cavity (25-40%) [13][14][15][16]. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the stage at diagnosis [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31].…”

“…Among sinonasal cases, approximately 80% are located in the nasal cavity itself, most commonly the middle and inferior turbinates, lateral nasal wall and nasal septum, while 20% occur in the paranasal sinuses [13,15,16].…”

Integrated regulatory-metabolic network model reveals critical mechanism and potential targets for Hepatocellular Carcinoma

“…GSH is a key member of cell immune response system, lacking it can easily lead to cell death, several labs have confirmed its common occurrence in all cancers (41) and considered it as potential therapeutic target. Besides, the loss of SLC25A11, the enzyme catalyzing these reactions, has been validated to inhibit tumor cell growth in non-small cell lung cancer (42). Baulies et al (43) suggested that the over-expression of SLC25A11 works as an adaptive mechanism of HCC to provide enough GSH for vast cell growth, meanwhile, SLC25A11 induced exportation of AKG to cytosol also activates mTOR pathway to promote cell growth and anabolism through EGLNs (egl-9 family hypoxia-inducible factors) (44).…”