SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer

Abstract

Lung cancer is one of the leading causes of cancer-related death in developed countries. Despite decades of intensive efforts to comate this malignant disease, the prognosis of lung cancer remains unfavorable and is especially poor in advanced non-small cell lung cancer (NSCLC). Accumulating evidence indicate that one of the main causes of the poor outcome in NSCLC treatment is the innate resistance of NSCLC patients to anticancer drugs. However, the mechanism underling NSCLC development and drug resistance is not fully understood. Here we show that the mitochondrial class III NAD(+)-dependent deacetylase SIRT5 is overexpressed in human NSCLC and high expression of SIRT5 predicts poor survival. SIRT5 knockdown represses lung cancer cell growth and transformation in vitro and in vivo. Furthermore, we find that SIRT5 knockdown makes lung cancer cells more sensitive to drug (cis-diamminedichloroplatinum [CDDP], 5-fluorouracil [5-FU] or bleomycin) treatment in vitro and in vivo. Mechanically, we identify Nrf2, which is a core transcription factor for lung cancer growth and drug resistance, as a target of SIRT5. SIRT5 mRNA level is positively correlated with the expression of Nrf2 in lung cancer tissues and SIRT5 knockdown reduces the expression of Nrf2 and its downstream drug-resistance genes. Taken together, our findings implicate that SIRT5 as a protein responsible for growth and drug resistance in human NSCLC, and SIRT5 may serve as a potential prognostic factor and drug target for intervention.

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…NRF2 is a transcription factor that regulates development and drug resistance of human NSCLC (24). NSCLCs show NRF2 upregulation, and SIRT5 KD resulted in reduced NRF2 levels, and expression of downstream targets of NRF2 (94). These observations highlighted the potential role of SIRT5 in promoting lung cancer growth and drug resistance, by promoting the expression of NRF2 and its downstream targets (94).…”

“…NSCLCs show NRF2 upregulation, and SIRT5 KD resulted in reduced NRF2 levels, and expression of downstream targets of NRF2 (94). These observations highlighted the potential role of SIRT5 in promoting lung cancer growth and drug resistance, by promoting the expression of NRF2 and its downstream targets (94). Another study proposed that SIRT5-mediated SOD1 desuccinylation and activation might be relevant in lung tumor cell growth (88).…”

“…It is possible that SIRT5 contributes to metabolic reprogramming in cancer cells, potentially by participating in PDC inhibition. Very recently, Lu et al showed that SIRT5 is overexpressed in advanced non-small cell lung cancer (NSCLC), and that SIRT5 KD repressed the growth rate of NSCLC cell lines (94). SIRT5 KD in these cells increased their susceptibility to genotoxic drugs (94).…”

“…Very recently, Lu et al showed that SIRT5 is overexpressed in advanced non-small cell lung cancer (NSCLC), and that SIRT5 KD repressed the growth rate of NSCLC cell lines (94). SIRT5 KD in these cells increased their susceptibility to genotoxic drugs (94). NRF2 is a transcription factor that regulates development and drug resistance of human NSCLC (24).…”

“…These results highlight a potential role of SIRT5 in the defense mechanisms of cancer cells against ROS-induced apoptosis, by promoting SOD1 activity. In this context, Lu et al showed that SIRT5 is overexpressed in NSCLC, and SIRT5 KD results in the repression of NSCLC cells growth (94). In addition, SIRT5 represses the activities of PDC and SDH (116), both of which have a critical role in cancer cell metabolic reprogramming, and PDC activity is suppressed in many types of tumor cells.…”