Curcumin inhibits 3T3-L1 preadipocyte proliferation by mechanisms involving post-transcriptional p27 regulation

Abstract

Previous reports from our lab have shown that Skp2 is necessary for p27 degradation and cell cycle progression during adipocyte differentiation. Data presented here demonstrate that the anti-inflammatory, anti-obesity phytochemical curcumin blocked Skp2 protein accumulation during early adipocyte hyperplasia. In addition, curcumin dose-dependently induced p27 protein accumulation and G1 arrest of synchronously replicating 3T3-L1 preadipocytes. Of note, p27 protein accumulation occurred in the presence of decreased p27 mRNA suggesting a role for post-transcriptional regulation. In support of this hypothesis, curcumin markedly increased p27 protein half-life as well as attenuated ubiquitin proteasome activity suggesting that inhibition of targeted p27 proteolysis occurred through curcumin-mediated attenuation of Skp2 and 26S proteasome activity. While we observed no cytotoxic effects for curcumin at doses less than 20 µM, it is important to note an increase in apoptotic signaling at concentrations greater than 30 µM. Finally, data presented here demonstrate that the anti-proliferative effect of curcumin was critical for the suppression of adipocyte differentiation and the development of the mature adipocyte. Collectively, our data demonstrate that curcumin-mediated post-transcriptional accumulation of p27 accounts in part for the anti-proliferative effect observed in 3T3-L1 preadipocytes.

miR-107 inhibits CDK6 expression, differentiation, and lipid storage in human adipocytes

“…Therefore, inhibition of CDK6 mediated phosphorylation of Rb could cause G1 phase arrest (Pekkonen et al, 2014). A cell cycle arrest in the G1 phase has been shown to inhibit differentiation in 3T3-L1 adipocytes (Ferguson et al, 2016;Auld and Morrison, 2006;Auld et al, 2007). When CDK6 was silenced, Notch3 and its targets Hes1 and Hey1, were decreased (Pekkonen et al, 2014).…”

Kbtbd11 gene expression in adipose tissue increases in response to feeding and affects adipocyte differentiation

“…Cyclin D1 functions as a key sensor for mitogenic stimuli and promotes cell cycle progression from the G1 to S phase . In contrast, p27, a cyclin‐dependent kinase inhibitor, is a key negative regulator of the cell cycle during progression from the G1 to S phase . The balance of the cyclin D1‐p27 control system might play an important role in MCE.…”

“…15 In contrast, p27, a cyclin-dependent kinase inhibitor, is a key negative regulator of the cell cycle during progression from the G1 to S phase. 16 The balance of the cyclin D1-p27 control system might play an important role in MCE. After MCE, CEBPB activates Cebpa and Pparg, which then transcriptionally activate genes that give rise to the adipocyte phenotype.…”

Antidiabetic Properties of Curcumin I: Evidence from In Vitro Studies

“…Curcumin treatment reduced S-phase kinase-associated protein 2 (Skp2) protein accumulation and induced p27 protein accumulation and G1 arrest. p27 mRNA levels and ubiquitin proteasome activity were reduced with curcumin treatment, suggesting that p27 proteolysis is mediated by the attenuation of Skp2 and proteasome activity [63].…”

“…Treatment of 3T3-L1 preadipocytes with curcumin (20 µM) for 72 h resulted in significantly reduced adipocyte differentiation and development of mature adipocytes [63]. Curcumin treatment reduced S-phase kinase-associated protein 2 (Skp2) protein accumulation and induced p27 protein accumulation and G1 arrest.…”