Ornithine aminotransferase promoted the proliferation and metastasis of non‐small cell lung cancer via upregulation of miR‐21

Abstract

The incidence and mortality of lung cancer ranked the first among all types of cancer in China, and non‐small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for 85% of all lung cancers. Given that the survival rate of patients with advanced NSCLC is still poor nowadays, identification of novel therapeutic targets and the development of effective therapies are desired for the treatment of NSCLC in clinics. In this study, we reported the upregulation of ornithine aminotransferase (OAT) in NSCLC cells and clinical tumor samples as well as its association with the advanced TNM stage, metastasis, and poor tumor differentiation of lung cancer. Using different NSCLC cell lines, we demonstrated that OAT promoted the proliferation, invasion, and migration, inhibited the apoptosis, and altered cell cycle of NSCLC cells; besides, the involvement of OAT‐miR‐21‐glycogen synthase kinase‐3β signaling in the functional role of OAT in NSCLC was also revealed. Importantly, in the absence of OAT, the growth and metastasis of tumor lung cancer xenograft was significantly suppressed in the nude mice. Based on our findings, OAT may be a potential novel biomarker for the diagnosis and therapeutic outcome monitoring of NSCLC. Inhibition of OAT may also represent a new therapeutic strategy of NSCLC.

The Janus-like role of proline metabolism in cancer

“…The role of P5CS is likely to be context-specific, as, in breast cancer, CRISPR/Cas9-mediated knockout of P5CS had no impact on tumor growth, but it sensitized cancer cells to pharmacological inhibition of lipogenesis, indicating that inhibition of proline biosynthesis could synergize with therapies targeting lipid metabolism 122 . Recently, increased expression of OAT has been shown to correlate with NSCLC progression, and OAT activity supports proliferation and metastatic spread of NSCLC cells 126 .…”

Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer

“…A manual investigation of the GSMM flux profiles revealed three likely reasons for the essentiality of ASL : 1) compromised proline synthesis via OAT accompanied by 2) decreased fumarate production for the TCA cycle and 3) decreased OAA to aspartate conversion that compromises aminotransferase activity and therefore anaplerotic fueling of the TCA cycle. In addition to ASL, we identified six other significant targets from the gene essentiality analysis, most of which have been associated with poor cancer survival 6 , 43 – 45 . For example, increased expression of the IDH2 gene has been shown to be overexpressed in endometrial, prostate, testicular, and advanced colon cancer 46 – 48 , and we have recently demonstrated that IDH2 indeed fuels reductive glutaminolysis and fatty acid synthesis in the D492 and D492M cells in an accompanying study 49 .…”

Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity

“…38 OAT stimulated the proliferation, migration, and invasion and blocked the apoptosis, while the lack of OAT reduced the growth and metastasis of lung cancer xenograft. 39 Hence, P4 reduction of OAT levels may be beneficial in terms of growth and invasion suppression in GBM. Three hundred µM P4 increased the levels of the mitochondrial ATP synthase subunit beta (ATP5F1B, UniProt ID: P06576).…”