Metformin and tenovin‐6 synergistically induces apoptosis through LKB1‐independent SIRT1 down‐regulation in non‐small cell lung cancer cells

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.

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer

“…Previously, the SIRT family has been reported to serve a critical part in the process of tumorigenesis (25)(26)(27). Each individual SIRT may act either as a tumor suppressor or an oncogene in different types of malignancies, potentially via tumor-associated signaling pathways or mitosis regulation (13,28,29). However, the specific association between SIRTs and OC remains controversial, and remains to be further clarified.…”

circRNA-miRNA-mRNA regulatory network in human lung cancer: an update

“…CircRNAs included in our study were divided into 7 parts according to their clinical characteristics. As we can see in the picture, most of the circRNAs are significantly related to lymphatic metastasis and TNM stage cancer cell [118]. has_circ_001569 preforms its function by miRNA-148a, enhancing Wnt/β-catenin pathway associated gene expression [119].…”

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

“…Tenovin-6, an inhibitor of both SIRT1 and SIRT2, in combination with metformin, an antidiabetic drug and mTOR signaling pathway inhibitor, caused cell growth inhibition and induced apoptosis in lung cancer cells (Lee et al, 2019). Additionally, a preclinical study identified the synergistic interaction of ricolinostat and ibrutinib the first-in-class BTK (Bruton's tyrosin kinase) inhibitor in a large panel of lymphoma cell lines and in a xenograft model of lymphoma.…”