Mitochondrial glutamine metabolism via GOT2 supports pancreatic cancer growth through senescence inhibition

Abstract

Cellular senescence, which leads to a cell cycle arrest of damaged or dysfunctional cells, is an important mechanism to restrain the malignant progression of cancer cells. Because metabolic changes underlie many cell-fate decisions, it has been suggested that cell metabolism might play key roles in senescence pathways. Here, we show that mitochondrial glutamine metabolism regulates senescence in human pancreatic ductal adenocarcinoma (PDAC) cells. Glutamine deprivation or inhibition of mitochondrial aspartate transaminase (GOT2) results in a profound induction of senescence and a suppression of PDAC growth. Glutamine carbon flow through GOT2 is required to create NADPH and to maintain the cellular redox state. We found that elevated reactive oxygen species levels by GOT2 knockdown lead to the cyclin-dependent kinase inhibitor p27-mediated senescence. Importantly, PDAC cells exhibit distinct dependence on this pathway, whereas knockdown of GOT2 did not induce senescence in non-transformed cells. The essentiality of GOT2 in senescence regulation of PDAC, which is dispensable in their normal counterparts, may have profound implications for the development of strategies to treat these refractory cancers.

Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer

“…Furthermore, five of the seven glycolytic and PPP enzymes identified in our interactome analysis (GOT2, GPI, PGD, PSAT1, and TKT) were found to map to the “Metabolic reprogramming in colon cancer” pathway. Previously, inhibition of glutamic oxaloacetic transaminase 2 (GOT2) has been shown to lead to elevated levels of reactive oxygen species (ROS) and cyclin‐dependent kinase inhibitor p27‐mediated cell senescence in human pancreatic ductal adenocarcinoma cells (Yang et al , ). Disruption of glucose‐6‐phosphate isomerase (GPI), in turn, has been shown to reduce glucose consumption and suppress lactic acid secretion in the LS174T CRC cell line, resulting in reprogramming of cells to depend on oxidative phosphorylation and mitochondrial ATP production (de Padua et al , ).…”

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

“…p53 increases the activation of p21 transcription, thereby facilitating cellular senescence . As a putative candidate for cancer treatment, p53/p21 signaling exerts a potent effect on senescence in various digestive system tumors, including HCC, colorectal cancer, gastric cancer and pancreatic cancer …”

“…6 As a putative candidate for cancer treatment, p53/p21 signaling exerts a potent effect on senescence in various digestive system tumors, including HCC, 7 colorectal cancer, 8 gastric cancer 9 and pancreatic cancer. 10 Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs. Synthesized by back-splicing in which the head-to-tail splice junctions are joint together to form a circular transcript, circRNAs are conserved, stable, abundant, and expressed in a tissue-specific and cell-specific manner.…”

Preventing BRCA1/ZBRK1 repressor complex binding to the GOT2 promoter results in accelerated aspartate biosynthesis and promotion of cell proliferation

“…elucidated a novel mechanism whereby SIRT3‐dependent GOT2 acetylation affects the malate–aspartate NADH shuttle activity and promotes pancreatic tumor growth (Yang et al ., ). Additionally, GOT2 overexpression could inhibit senescence of pancreatic tumor cells and therefore contribute to tumor progression (Yang et al ., ). Thus, it is reasonable to propose that GOT2 is a metabolic hub, providing cells with aspartate and/or α‐KG for energy demands and biosynthetic processes.…”

“…Thus aspartate synthesis is essential for cancer progression. Actually, aspartate metabolism reprogramming exists in many cancers, including hepatocellular carcinoma (Darpolor et al ., ), pancreatic cancer (Yang et al ., , ), leukemia (Sullivan et al ., ), lung cancer, cervical cancer, osteosarcoma and glioblastoma (Sullivan et al ., ). GOT2 converts glutamate and oxaloacetate to generate aspartate and α‐KG, which is the critical enzyme for maintaining the aspartate pool (Feist et al ., ).…”