SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer

Abstract

Abnormal lipid metabolism has been commonly observed in various human cancers, including colorectal cancer (CRC). The mitochondrial citrate carrier SLC25A1 (also known as mitochondrial citrate/isocitrate carrier, CIC), has been shown to play an important role in lipid metabolism regulation. Our bioinformatics analysis indicated that SLC25A1 was markedly upregulated in CRC. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in CRC remain unexplored. Here, we found that SLC25A1 expression was significantly increased in tumor samples of CRC as compared with paired normal samples, which is associated with poor survival in patients with CRC. Knockdown of SLC25A1 significantly inhibited the growth of CRC cells by suppressing the progression of the G1/S cell cycle and inducing cell apoptosis both in vitro and in vivo, whereas SLC25A1 overexpression suppressed the malignant phenotype. Additionally, we demonstrated that SLC25A1 reprogrammed energy metabolism to promote CRC progression through two mechanisms. Under normal conditions, SLC25A1 increased de novo lipid synthesis to promote CRC growth. During metabolic stress, SLC25A1 increased oxidative phosphorylation (OXPHOS) to protect protects CRC cells from energy stress-induced cell apoptosis. Collectively, SLC25A1 plays a pivotal role in the promotion of CRC growth and survival by reprogramming energy metabolism. It could be exploited as a novel diagnostic marker and therapeutic target in CRC.

Accumulation of oncometabolite D-2-Hydroxyglutarate by SLC25A1 inhibition: A metabolic strategy for induction of HR-ness and radiosensitivity

“…The mechanisms of IR-induced cell death depend on many factors including the cell line, radiation dosage, and the state of the cell [ 38 ]. Here, our observation of CTPI2-induced apoptosis and cell death was in good accordance with the recent discovery in colorectal cancer, which indicated that knockdown of SLC25A1 significantly inhibited colorectal tumor growth by inducing apoptosis both in vitro and in vivo [ 39 ]. These results further corroborated the lethal effect of SLC25A1-inhibition on cell function and DDR, resulting in suppression of cell reproduction.…”

Identifying targetable metabolic dependencies across colorectal cancer progression

“…We found that oxidative metabolism was maintained throughout CRC progression and was enhanced in the most progressed adenocarcinoma cells (M), supporting its consideration for therapeutic intervention (39, 47, 48). It has been shown that CRC cells consume more oxygen and contain more mitochondria than surrounding normal colonic tissue in vivo (49).…”

“…However, as our series of cell lines were initially derived from a polyp already harbouring aberrant WNT activation due to loss of both wild-type APC alleles, it is more likely that alternative underlying driver mutations account for changes in metabolism we see in our model. We found that oxidative metabolism was maintained throughout CRC progression and was enhanced in the most progressed adenocarcinoma cells (M), supporting its consideration for therapeutic intervention (39,47,48). It has been shown that CRC cells consume more oxygen and contain more mitochondria than surrounding normal colonic tissue in vivo (49).…”

Multiple roles played by the mitochondrial citrate carrier in cellular metabolism and physiology

“…Under nutrient-sufficient conditions, the CIC supplies acetyl units for fatty acid synthesis to promote tumor growth. During metabolic stress, it increases OXPHOS to protect cancer cells from energy stress-induced cell apoptosis [ 93 ]. In fact, the entry of malate into the mitochondria in exchange for citrate might impact upon mitochondrial respiration, the stability of mitochondrial membrane potential, as well as on glycolysis and on lipogenesis [ 94 ].…”