Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD+ reduction
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Baiyun Wang1,2,3, Xue Chen2, Zixi Wang2, Wei Xiong3, Tao Xu3, Xinyuan Zhao3, Yang Cao3, Yanru Guo2, Lin Li3, She Chen3, Song Huang3, Xiaodong Wang3, Min Fang2 and Zhirong Shen3
1Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, 100084, China
2Joint Center for Life Sciences, and School of Life Sciences, Peking University, Beijing, 100871, China
3National Institute of Biological Sciences, Beijing, 102206, China
Zhirong Shen, email: [email protected]
Min Fang, email: [email protected]
Keywords: aldehyde dehydrogenase, lung cancer, glutathione, dihydrolipoic acid, NAD+/NADH ratio
Received: December 15, 2016 Accepted: April 07, 2017 Published: May 08, 2017
Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.
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