The Role And Mechanism Of Hypoxia Regulated Mitochondrial NADPH Synthesis In Cancer Progression

Hypoxia is one of the central characteristics of the microenvironment developed by solid tumors. Hypoxia-inducible factors, including HIF-1? and HIF-2?, play a critical role in metabolism reprogramming of cancer cells under hypoxia and thus promote the survival and proliferation of cancer cells. Hence, we believe a more detailed dissection of the mechanism that cancer cells adapt to hypoxia will contribute to the discovery of potential therapeutic targets and new approaches towards cancer diagnosis and therapy.Mitochondria, the metabolic factory inside cell, is the most important metabolic organelle and its functional changes are closely related with cancer progression including tumor initiation, growth, survival and metastasis. Here we show that HCC cells undergo a series of metabolic reprogramming under hypoxia condition, and notably the NADPH synthesis inside mitochondria is also reprogrammed. Besides, we demonstrated that HIF-1?, stabilized under hypoxia, promotes the synthesis of NADPH in mitochondria by inducing the expression of NADK2 and NNT, which further affects the level of ROS and proliferation of HCC cells. Moreover we also found an aberrant expression of NADK2 and NNT in liver cancer tissues. Therefore,this study reveals the mechanism and significance of NADPH synthesis reprogramming inside mitochondria of HCC cells under hypoxia, and thus provides a new direction and target for the diagnosis and treatment of liver cancer.