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Sirtuin 2 knockdown inhibits cell proliferation and RAS/ERK signaling, and promotes cell apoptosis and cell cycle arrest in multiple myeloma.

ABSTRACT: The present study aimed to explore the regulatory role of sirtuin 2 (SIRT2) in malignant progression of multiple myeloma (MM) and the potential associated signaling pathways. In total, 30 patients with MM and 15 healthy bone marrow donors were enrolled in the current study and their bone marrow samples were collected to isolate the plasma cells. The expression levels of SIRT2 were detected in MM cell lines (KMS‑28BM, U266, RPMI‑8226 and NCI‑H929) and normal plasma cells (collected from healthy bone marrow donors as the control) via reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. SIRT2 knockdown was established by transfecting two MM cell lines (RPMI‑8226 and NCI‑H929 cells) with short hairpin RNA‑SIRT2 recombinant plasmid; the control group was transfected with a control recombinant plasmid. Subsequently, the effect of SIRT2 knockdown on MM cell proliferation, apoptosis, cell cycle progression and RAS/ERK signaling was investigated via Cell Counting Kit‑8, flow cytometry, RT‑qPCR and western blot assays, respectively. The mRNA and protein expression levels of SIRT2 were increased in U266 (P<0.001), KMS‑28BM (P<0.001), RPMI‑8226 (P<0.001) and NCI‑H929 (P<0.001) cells compared with those in the control cells. In NCI‑H929 and RPMI‑8226 cells, cell proliferation was decreased 48 h (P<0.05) and 72 h (P<0.05) after SIRT2 knockdown. Furthermore, the cell apoptotic rate was elevated 48 h after SIRT2 knockdown (P<0.01). In addition, the percentage of cells at the G0/G1 phase was increased (P<0.01), whereas the percentage of cells at the S phase was reduced (P<0.01) 48 h after SIRT2 knockdown. The expression levels of HRAS and phosphorylated‑ERK were also reduced 48 h after SIRT2 knockdown. In conclusion, SIRT2 was highly expressed in MM cell lines, and knockdown of SIRT2 inhibited MM cell proliferation, inactivated the RAS/ERK signaling pathway, and promoted cell apoptosis and cell cycle arrest.

SUBMITTER: Ding T

PROVIDER: S-EPMC8436222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin, THC) is a major bioactive metabolite of curcumin (the principal active ingredient of Curcuma longa L.), and overcomes the low bioavailability of curcumin, demonstrating the potential anti-inflammatory, antioxidant and neuroprotective properties, etc, some of which were considered to be even superior to curcumin. In the present study, the protective properties of THC in the hippocampus of APP/PS1 mice, and the effects of THC against Aβ-induced toxicity in BV-2 cells were explored. The data in vitro showed that Aβ induced decreased cell viability, and cell cycle arrest and apoptosis in BV-2 cells, which could be ameliorated by THC. In vivo, THC administration was able to rescue learning and memory, and reduce Aβ burden in the hippocampus of APP/PS1 mice. By comprehensive proteomic analysis of the hippocampus of mice, a total of 157 differentially expressed proteins were identified in APP/PS1 mice treated with THC (comparing with APP/PS1 mice), which were enriched in “T cell activation”, “lymphocyte proliferation” and “protein oligomerization”, etc. The results of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that the effects of THC on the cell cycle and apoptosis were mostly related to the “Ras signaling pathway” and “JAK−STAT signaling pathway”, etc. Using Western blot and ELISA, the down-regulation of Gab2 and K-Ras, and the up-regulation of caspase-3, TGF-β1 and TNF-ɑ were found in APP/PS1 mice. THC attenuated the abnormal expression of Gab2, K-Ras, caspase-3 and TNF-ɑ, and up-regulated Bag1 and TGF-β1 expression in APP/PS1 mice. In BV-2 cells, Aβ induced the down-regulation of Gab2, K-Ras and TGF-β1, and the overexpression of caspase-3, PARP1, cleaved-PARP1 and TNF-ɑ, which were markedly restored by THC. Moreover, THC up-regulated Bag1 expression in BV-2 cells treated with Aβ. The decreased transcriptional expression levels of Ccnd2 and Cdkn1a was also observed in Aβ-treated BV-2 cells. THC treatment alleviated down-regulation of Ccnd2, but did not affect the abnormal transcriptional expression of Cdkn1a caused by Aβ in BV-2 cells. For the first time, we identified that the action of THC in preventing AD was associated with inhibition of cell cycle arrest and apoptosis of microglia via the Ras/ERK signaling pathway, shedding new light on the role of THC in alleviating the progression of AD.

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Sirtuin 2 knockdown inhibits cell proliferation and RAS/ERK signaling, and promotes cell apoptosis and cell cycle arrest in multiple myeloma.

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