SIRT3 promotion reduces resistance to cisplatin in lung cancer by modulating the FOXO3/CDT1 axis

Abstract

Abstract Background Cisplatin is an extensively used chemotherapy agent for lung cancer, but its drug resistance serves as a huge obstacle for chemotherapy failure of lung cancer patients. Hence, researchers aimed to determine role of sirtuin 3 (SIRT3) considering its action in cisplatin resistance of lung cancer. Methods The expression patterns of SIRT3, FOXO3, and CDT1 were determined using RT‐qPCR and Immunoblotting in lung cancer. Immunofluorescence and Co‐IP were adopted to detect co‐localization and interaction of FOXO3 and CDT1. Loss‐ and gain‐function assays were conducted to determine roles of SIRT3, FOXO3, and CDT1 in resulting pathological changes, while biological behavior of cells was determined using a combination of CCK‐8, flow cytometry, colony formation, and Transwell assays. The effects of SIRT3 and CDT1 were determined in the nude mice xenografted with the tumor. The proliferation‐, angiogenesis‐, and apoptosis‐associated factors levels were determined using Immunoblotting. Results SIRT3, FOXO3, and CDT1 expression was suppressed in the lung cancer tissues and cells. FOXO3 positively regulates the CDT1 expression pattern and SIRT3 elevation inhibits FOXO3 at the acetylated level, thus, elevating FOXO3 expression. The elevation of SIRT3, FOXO3, or CDT1 inhibited cell cisplatin resistance of lung cancer cells as well as inhibited viability, proliferation, and invasion in vitro. In vivo experiments, SIRT3 depletion elevated Ki‐67 and VEGFA levels, but downregulated cleaved caspase 3 level. Conclusion Collectively, overexpressed SIRT3 elevates expression of FOXO3a/CDT1 axis, thus, contributing to enhanced sensitivity of lung cancer cells.

Keywords

• chromatin licensing and DNA replication factor 1
• cisplatin
• Forkhead box O3a
• lung cancer
• sirtuin 3