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Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD⁺ reduction.

ABSTRACT: 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.

SUBMITTER: Wang B

PROVIDER: S-EPMC5620155 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD+ reduction.

Wang Baiyun B Chen Xue X Wang Zixi Z Xiong Wei W Xu Tao T Zhao Xinyuan X Cao Yang Y Guo Yanru Y Li Lin L Chen She S Huang Song S Wang Xiaodong X Fang Min M Shen Zhirong Z

Oncotarget 20170508 40

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 ...[more]

PMID: 28978015

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Project description:BACKGROUND: We showed there are specific ALDH1 autoantibodies in ovarian autoimmune disease and ovarian cancer, suggesting a role for ALDH1 in ovarian pathology. However, there is little information on the ovarian expression of ALDH1. Therefore, we compared ALDH1 expression in normal ovary and benign and malignant ovarian tumors to determine if ALDH1 expression is altered in ovarian cancer. Since there is also recent interest in ALDH1 as a cancer stem cell (CSC) marker, we assessed co-expression of ALDH1 with CSC markers in order to determine if ALDH1 is a potential CSC marker in ovarian cancer. METHODS: mRNA and protein expression were compared in normal human ovary and serous ovarian tumors using quantitative Reverse-Transcriptase PCR, Western blot (WB) and semi-quantitative immunohistochemistry (IHC). ALDH1 enzyme activity was confirmed in primary ovarian cells by flow cytometry (FC) using ALDEFLUOR assay. RESULTS: ALDH1 mRNA expression was significantly reduced (p < 0.01; n = 5) in malignant tumors compared to normal ovaries and benign tumors. The proportion of ALDH1+ cells was significantly lower in malignant tumors (17.1 ± 7.61%; n = 5) compared to normal ovaries (37.4 ± 5.4%; p < 0.01; n = 5) and benign tumors (31.03 ± 6.68%; p < 0.05; n = 5). ALDH1+ cells occurred in the stroma and surface epithelium in normal ovary and benign tumors, although surface epithelial expression varied more in benign tumors. Localization of ALDH1 was heterogeneous in malignant tumor cells and little ALDH1 expression occurred in poorly differentiated malignant tumors. In benign tumors the distribution of ALDH1 had features of both normal ovary and malignant tumors. ALDH1 protein expression assessed by IHC, WB and FC was positively correlated (p < 0.01). ALDH1 did not appear to be co-expressed with the CSC markers CD44, CD117 and CD133 by IHC. CONCLUSIONS: Total ALDH1 expression is significantly reduced in malignant ovarian tumors while it is relatively unchanged in benign tumors compared to normal ovary. Thus, ALDH1 expression in the ovary does not appear to be similar to breast, lung or colon cancer suggesting possible functional differences in these cancers. SIGNIFICANCE: These observations suggest that reduced ALDH1 expression is associated with malignant transformation in ovarian cancer and provides a basis for further study of the mechanism of ALDH1 in this process.

Dataset Information

Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD⁺ reduction.

Publications

Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD<sup>+</sup> reduction.

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