Hypoxia-inducible Factor-1α Mediates Hyperglycemia-induced Pancreatic Cancer Glycolysis

Author(s): Liang Cheng, Tao Qin, Jiguang Ma, Wanxing Duan, Qinhong Xu, Xuqi Li, Liang Han, Wei Li, Zheng Wang, Dong Zhang, Qingyong Ma*, Jianjun Lei*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 12 , 2019

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Graphical Abstract:


Background: Recent studies have suggested that 85% of pancreatic cancer patients accompanied with impaired glucose tolerance or even Diabetes Mellitus (DM) and the invasive and migratory abilities of pancreatic cancer could be enhanced by high glucose. This study aimed to investigate whether Hypoxia- Inducible Factor-1α (HIF-1α) mediates hyperglycemia-induced pancreatic cancer glycolysis.

Methods: The cellular glycolytic activity was assessed by determining lactate production, glucose uptake and lactate dehydrogenase enzymatic activity. Pancreatic cancer cells (BxPC-3 cells) were transfected with short hairpin RNA targeting the HIF-1α.

Results: Hyperglycemia promotes pancreatic cancer glycolysis. Lactate dehydrogenase A (LDHA) activity and hexokinase 2 (HK2), platelet-type of phosphofructokinase (PFKP) expression were significantly upregulated under hyperglycemic conditions. HIF-1α knockdown prominently down-regulated the activity of LDHA and the expression of HK2, PFKP and decreased lactate production in BxPC-3 cells. Under hypoxia condition, hyperglycemia induced pancreatic glycolysis by mechanisms that are both dependent on HIF-1α and independent of it.

Conclusion: The accumulation of HIF-1α induced by hyperglycemia increases LDHA activity and HK2, PFKP expression, thereby promoting pancreatic glycolysis to facilitate cancer progression.

Keywords: Hyperglycemia, lactate dehydrogenase A, HIF-1α, glycolysis, pancreatic cancer.

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Year: 2019
Published on: 02 December, 2019
Page: [1503 - 1512]
Pages: 10
DOI: 10.2174/1871520619666190626120359
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