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HIF-2α regulates non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway in human pancreatic ductal adenocarcinoma.

Related Articles HIF-2α regulates non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway in human pancreatic ductal adenocarcinoma. J Cell Mol Med. 2017 Nov;21(11):2896-2908 Authors: Li W, Chen C, Zhao X, Ye H, Zhao Y, Fu Z, Pan W, Zheng S, Wei L, Nong T, Li Z, Chen R Abstract Hypoxia-inducible factor-2α (HIF-2α) plays an important role in increasing cancer progression and distant metastasis in a variety of tumour types. We aimed to investigate its biological function and clinical significance in human pancreatic ductal adenocarcinoma (PDAC). A total of 283 paired PDAC tissues and adjacent normal tissues were collected from patients who underwent surgery or biopsy at Sun Yat-sen Memorial Hospital between February 2004 and October 2016. In this study, we noted that HIF-2α expression was significantly up-regulated in PDAC, positively associated with disease stage, lymph-node metastasis and patient survival, and identified as an independent prognostic factor of PDAC patients. We demonstrated that HIF-2α silencing could reduce proliferation, migration and invasion of PDAC cells in vitro. The similar effect on growth was demonstrated in vivo. Furthermore, we noted that knock-down of HIF-2α significantly decreased the expression of glutamate oxaloacetate transaminase 1 (GOT1). Importantly, we confirmed that the PI3K/mTORC2 pathway promoted GOT1 expression by targeting HIF-2α. Our study validated HIF-2α was an important factor in PDAC progression and poor prognosis and may promote non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway. Targeting HIF-2α represents a novel prognostic biomarker and therapeutic target for patients with PDAC. PMID: 28544376 [PubMed - indexed for MEDLINE]

Prolonged hypoxia increases glutamine metabolism in PDAC cells, and HIF‐2α can promote non‐canonical glutamine metabolism in chronic hypoxic conditions. (A) Time course of glutamine consumption at 1%, 3% or 20% O2, each time data point is an average of triplicate experiments. (B) Panc‐1 and Capan‐2 were incubated for 48 hrs at 1%, 3% or 20% O2, GLS1, GOT1 and GOT2 protein were measured by Western blot. β‐Actin was used as loading control. (C) Panc‐1 and Capan‐2 were incubated for 48 hrs at 1%, 3% or 20% O2, GLS1, GOT1 and GOT2 mRNA were measured by qRT‐PCR. Data are presented as mean ± S.D. from three independent experiments. (D and F) Si‐HIF‐2α‐transfected Panc‐1 and Capan‐2 cultured at 1% or 3%O2 for 48 hrs. The level of HIF‐2α and glutamine metabolism enzymes mRNA and protein were determined by qRT‐PCR (mRNA) and Western blot (protein), and β‐actin was used as loading control. Data are presented as mean ± S.D. from three independent experiments. *P < 0.05, **P < 0.01.

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