Role of SIRT1/AMPK signaling in the proliferation, migration and invasion of renal cell carcinoma cells

Abstract

Renal cell carcinoma (RCC) is a lethal urologic tumor commonly seen in men that best responds to partial nephrectomy. An enhanced understanding of the molecular pathogenesis of RCC can broaden treatment options and tumor prevention strategies. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates several bioactive substances, and the present study aimed to identify the role of SIRT1/AMP-activated protein kinase (AMPK) signaling in RCC progression. SIRT1 expression was detected in 100 patients with RCC using tissue microarray immunohistochemistry. SIRT1-knockdown and overexpression were performed via RNA interference and plasmid transfection. Inhibition of AMPK was used for the phenotypic rescue assays to verify whether AMPK was a downstream target of SIRT1. Reverse transcription-quantitative PCR was performed to verify transfection efficiency. Transwell, MTT and flow cytometry apoptosis assays were performed to evaluate the migration, invasion, proliferation and early apoptosis level of RCC cells. SIRT1 and AMPK protein expression in human RCC tissues and cell lines (786-O and ACHN) was detected using western blotting and immunofluorescence staining. The current results, combined with data from The Cancer Genome Atlas database, revealed that SIRT1 expression in RCC tissues was downregulated compared with in adjacent normal tissues. Additionally, high SIRT1 expression was associated with an improved prognosis in patients with RCC. Overexpression of SIRT1 inhibited the proliferation, migration and invasion of RCC cell lines and induced apoptosis, while inhibition of SIRT1 expression had the opposite effects. Further experiments indicated that SIRT1 may serve an anticancer role by upregulating the expression levels of downstream AMPK, thus revealing a potential therapeutic target for RCC.

The sirtuin family in health and disease

“…[322][323][324] Effect of SIRT1 on cell proliferation: SIRT1 is involved in regulating cell proliferation in a bilateral way by regulating protein expression and acetylation. 272,325 The opposite effects of SIRT1 on cell proliferation have been observed among different cell types or the regulation of different downstream molecules. For example, SIRT1 promotes cell proliferation by regulating LC3 and retinoblastoma (Rb) acetylation.…”

“… 329 SIRT1 overexpression inhibits the proliferation of renal cancer cells, while inhibition of SIRT1 expression has the opposite effects. 325 SIRT1 might serve an anticancer role in cancer cells by upregulating expression of downstream AMPK. 330 SIRT1 also inhibits GC cell proliferation via the STAT3/matrix metalloproteinase (MMP)-13 signaling pathway.…”

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells

“…Using molecular docking simulations and cell-based studies, we herein demonstrated that both 4-dmH and heliomycin targeted SIRT1 and inhibited its activity and expression, to attenuate the growth of oral cancer cells. Given that SIRT1 contributes to a complex regulatory network, it is of primary importance to understand the fundamental regulatory mechanisms of SIRT1 in cell death regulation ( Wang et al, 2023 ; Wang et al, 2021a ; Lee et al, 2018 ; Zhu et al, 2020 ; Ran et al, 2023 ; Zhang et al, 2020 ).…”

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells

“…Using molecular docking simulations and cell-based studies, we herein demonstrated that both 4-dmH and heliomycin targeted SIRT1 and inhibited its activity and expression, to attenuate the growth of oral cancer cells. Given that SIRT1 contributes to a complex regulatory network, it is of primary importance to understand the fundamental regulatory mechanisms of SIRT1 in cell death regulation [57][58][59][60][61][62].…”