Resveratrol attenuates norepinephrine-induced ovarian cancer invasiveness through downregulating hTERT expression

Abstract

Stress hormone norepinephrine (NE) has been associated with acquisition of cancer progression, and naturally occurring phytoalexin resveratrol (REV) has been known to suppress cancer growth and progression. In the present study, we determine the effect of REV on NE-induced ovarian cancer invasiveness. Pretreatment of REV significantly inhibited NE-induced ovarian cancer cell epithelial-to-mesenchymal transition with concomitant recovery of E-cadherin expression. In addition, our data showed that REV downregulates NE-induced human telomerase reverse transcriptase (hTERT) expression through inhibiting Src phosphorylation and HIF-1α expression. Further, REV reduced NE-induced Slug expression and subsequent ovarian cancer invasion. More importantly, combined treatment of REV with a pharmacological inhibitor of beta adrenergic receptor significantly attenuated NE-induced ovarian cancer invasion compared to single treatment. Therefore, we demonstrate interference of a Src and HIF-1α/hTERT/Slug signaling cascade by REV, providing potential therapeutic targets and inhibition of ovarian cancer.

Rab25 augments cancer cell invasiveness through a β1 integrin/EGFR/VEGF-A/Snail signaling axis and expression of fascin

“…PVDF membranes with proteins were blocked and incubated for 2 h at room temperature, as described previously. 26 , 27 An E-cadherin antibody (610182) was purchased from BD Biosciences (San Jose, CA, USA). Antibodies for Rab25 (4314), Snail (3879), VEGFR-1 (2893) and p-EGFR (4407) were obtained from Cell Signaling Inc. (Danvers, MA, USA).…”

MicroRNA-532 and microRNA-3064 inhibit cell proliferation and invasion by acting as direct regulators of human telomerase reverse transcriptase in ovarian cancer

“…The up-regulation of hTERT in various tumor types has been shown to be critical for the acquisition and maintenance of the metastatic ability of tumor cells, through promoting tumor growth and angiogenesis and by stimulating EMT, invasiveness and stemness of tumor cells [4–9, 22]. Although altered expression of several miRNAs has been involved in the regulation of hTERT [12–15], the epigenetic mechanisms that caused elevated hTERT expression in OC remain poorly characterized.…”

“…hTERT is widely expressed in more than 85% of human tumors including OC [4], and it has been shown to promote the epithelial-to-mesenchymal transition (EMT), invasion and proliferation of OC cells [5, 6]. The transcriptional factor Slug is a well-documented EMT initiator in different cancers [7, 8], and hTERT induces OC cell invasion by upregulating Slug expression [5, 9]. The siRNA-mediated knockdown of hTERT and targeted inhibition of telomerase activity using the telomerase inhibitor BIBR1532 decreased hTERT expression and inhibited the proliferation and invasion of tumor cells [10, 11].…”

Telomerase Regulation from Beginning to the End

“…For example, a c-Myc and hypoxia-inducible factor(HIF)-α mediated induction of hTERT expression was recently reported for the stress hormone norepinephrine, contributing to invasiveness and metastasis of ovarian cancer [ 142 ]. This transcription induction may be therapeutically targetable, for example as the phytoalexin resveratrol was demonstrated to attenuate norepinephrine-induced Src phosphorylation by protein kinase A (PKA) and subsequent HIF-α expression, thus reducing hTERT expression in ovarian cancer cell lines [ 143 ].…”