SIRT1 Regulates the Chemoresistance and Invasiveness of Ovarian Carcinoma Cells

Abstract

BACKGROUND: SIRT1 is a longevity gene that forestalls aging and age-related diseases including cancer, and has recently attracted widespread attention due to its overexpression in some cancers. We previously identified the overexpression of SIRT1 in ovarian carcinoma (OvCa) as a poor prognostic factor. However, mechanistic insights into the function of SIRT1 in OvCa have yet to be elucidated. METHODS: Quantitative real-time reverse PCR (qRT-PCR) and Western blotting were employed to examine the expression of SIRT1 in a panel of human OvCa cell lines. si-RNA or sh-RNA and cDNA technologies were utilized to knockdown or overexpress SIRT1, respectively. The effects of SIRT1 on proliferation and chemoresistance were examined using a WST-1 assay, and the underlying mechanisms were confirmed using an apoptotic assay, and the quantification of glutathione (GSH), and reactive oxygen species (ROS). The aggressiveness of SIRT1 was analyzed using in vitro invasion and migration assays. RESULTS: SIRT1 was more strongly expressed in OvCa cell lines than in the immortalized ovarian epithelium at the gene and protein levels. Stress up-regulated the expression of SIRT1 in dose- and time-dependent manners. SIRT1 significantly enhanced the proliferation (P < .05), chemoresistance (P < .05), and aggressiveness of OvCa cells by up-regulating multiple antioxidant pathways to inhibit oxidative stress. Further study into the overexpression of SIRT1 demonstrated the up-regulation of several stemness-associated genes and enrichment of CD44v9 via an as-yet-unidentified pathway. CONCLUSIONS: Our results suggest that SIRT1 plays a role in the acquisition of aggressiveness and chemoresistance by OvCa, and has potential as a therapeutic target for OvCa.

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

“…Conversely, over-expression of SIRT1 was frequently observed in all kinds of non-melanoma skin cancers, including squamous cell carcinoma, basal cell carcinoma, Bowen's disease, and actinic keratosis [41,42]. Additionally, expression of SIRT1 was more strongly expressed in OVCA3 cells than in immortalized ovarian surface epithelium OSE7E cells [43]. In particular, over-expression of SIRT1 is correlated with lymph node metastasis and the decrease of the 5-year survival rate, indicating its oncogenic effects in ovarian cancer [40,42].…”

Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway

“…Because overexpression of SIRT1 reportedly renders cancer cells resistant to anti-cancer drugs [18,19], we examined SIRT1 levels in multidrug-resistant LS513 cells. ActD upregulated SIRT1 expression while Rp1 attenuated this effect to enhance cell death, as determined by increased PARP cleavage (Figure 2A).…”

Compounds from the Roots of Codonopsis pilosula and Their SIRT1 Regulatory Activity

“…Twelve known compounds were identified as perlolyrin (4) [8,9], 3-(9H-β-carbolin-1-yl)acrylic acid methyl ester (5) [8,9] [19][20][21]. However, SIRT1 is also a double-edged sword exemplified by tumor, it functions as an oncogene as well as a tumor suppressor [22]. Considering the traditional medicinal uses of the roots of C. pilosula and the roels of SIRT1 activation in energy metabolism [23], all the isolates were therefore examined for their regulatory activity on SIRT1.…”