Abstract
Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non‐histone proteins; however, antitumour effects by suppressing SIRT1 activity in non‐small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin‐6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin‐fixed paraffin‐embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence‐free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin‐6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin‐6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin‐6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1‐deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up‐regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase‐3‐dependent apoptosis. The study concluded that metformin with tenovin‐6 may enhance antitumour effects through LKB1‐independent SIRT1 down‐regulation in NSCLC cells.
Highlights
Failure to achieve long‐ lasting efficacy with a single agent has been observed because cancer cells can acquire resistance during long‐term treatment with a single agent such as epithelial growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) or anaplastic lymphoma kinase (ALK) inhibitor.[6,7]
This study explored whether the antiproliferative effect of the combination of metformin with tenovin‐6 was mediated by Sirtuin 1 (SIRT1) expression
These results suggest that the combined treatment of metformin and tenovin‐6 can synergistically induce the apoptotic pathway through SIRT1 down‐regulation in A549 cells
Summary
Lung cancer is the most common cause of cancer‐related death in the world. Despite significant advances in its diagnosis and treat‐ ment, its prognosis remains extremely poor.[1]. Metformin is an oral antidiabetic drug used to treat type II diabetes It is being tested as an anticancer agent because of its ability to suppress cancer growth in vitro and in vivo.[10-14]. Metformin and sorafenib can synergistically inhibit tumour growth by activating the AMPK pathway in NSCLC cells both in vitro and in vivo.[24]. The mechanism by which HIC affects SIRT1 down‐regulation has been explored, little is known about the mechanism involved in the regulation of anticancer activity of metformin in NSCLC cells by SIRT1. This study investigated a possible molecular mechanism of the anticancer effect of metformin plus SIRT1 inhibitor, tenovin‐6 in NSCLC cells irrespective of LKB1 status. Reverse (5′‐3′) CTGATTAAAAATGTCTCCACGAACAG CGTTGCTGTGCGAACTTGC CAAAGTTCCTTGTGCATCTTGG GCAAAGTAGAAAAGGGCGACAAC TCATAGCGTCGGTTGATGTCG GTAGCACACTCGACTTCC CCCATGATGAGATTGTACAGGA GGAGGTCATTCCAGTGAGTG CTGGGGAATGACCACTCTGT CCCTTGGCATCAGTTTCTGT CAGCAACGGAACAACCAAAG
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