Resveratrol inhibits Erk1/2‐mediated adhesion of cancer cells via activating PP2A–PTEN signaling network

Abstract

Resveratrol, a natural polyphenol compound, has been shown to possess anticancer activity. However, how resveratrol inhibits cancer cell adhesion has not been fully elucidated. Here, we show that resveratrol suppressed the basal or type I insulin-like growth factor (IGF)-1-stimulated adhesion of cancer cells (Rh1, Rh30, HT29, and HeLa cells) by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Inhibition of Erk1/2 with U0126, knockdown of Erk1/2, or overexpression of dominant-negative mitogen-activated protein kinase kinase 1 (MKK1) strengthened resveratrol's inhibition of the basal or IGF-1-stimulated of Erk1/2 phosphorylation and cell adhesion, whereas ectopic expression of constitutively active MKK1 attenuated the inhibitory effects of resveratrol. Further research revealed that both protein phosphatase 2A (PP2A) and phosphatase and tensin homolog (PTEN)-Akt were implicated in resveratrol-inactivated Erk1/2-dependent cell adhesion. Inhibition of PP2A with okadaic acid or overexpression of dominant-negative PP2A rendered resistance to resveratrol's suppression of the basal or IGF-1-stimulated phospho-Erk1/2 and cell adhesion, whereas expression of wild-type PP2A enhanced resveratrol's inhibitory effects. Overexpression of wild-type PTEN or dominant-negative Akt or inhibition of Akt with Akt inhibitor X strengthened resveratrol's inhibition of the basal or IGF-1-stimulated Erk1/2 phosphorylation and cell adhesion. Furthermore, inhibition of mechanistic/mammalian target of rapamycin (mTOR) with rapamycin or silencing mTOR enhanced resveratrol's inhibitory effects on the basal and IGF-1-induced inhibition of PP2A-PTEN, activation of Akt-Erk1/2, and cell adhesion. The results indicate that resveratrol inhibits Erk1/2-mediated adhesion of cancer cells via activating PP2A-PTEN signaling network. Our data highlight that resveratrol has a great potential in the prevention of cancer cell adhesion.

Disease-associated regulation of gene expression by resveratrol: Special focus on the PI3K/AKT signaling pathway

“…3 Treatment with resveratrol could decrease expression of miR-21 and finally decrease cancer cell survival; these events have been occurred after enhancing PTEN expression and blocking PI3K/AKT and mTOR pathways [94]. Also, resveratrol could decrease cancer cell survival and proliferation via inhibiting the ERK1/2 pathway [96,100] • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance…”

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma

“…RAC1 is widely expressed in cells where it mediates cell remodeling, membrane transport, transcriptional regulation, cell growth, and development [35]. A previous study has reported that BCAR1 and RAC1 also regulate cell movement and adhesion [36]. Specifically, RAC1-mediated cell migration is initiated by BCAR1 [37].…”

Resveratrol sensitizes A549 cells to irradiation damage via suppression of store‑operated calcium entry with Orai1 and STIM1 downregulation

“…At present, there are few studies indicating that the target of resveratrol may be associated with ERK1/2. When intracellular calcium is reduced to a certain limit, STIM1 protein is activated ( 50 ). This activation is mainly achieved through the phosphorylation of STIM1 protein at Ser575, Ser608 and Ser621, which are ERK1/2 target sites ( 51 ).…”