hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness

Abstract

Stress hormones have been implicated in both tumor initiation and progression. Human telomerase reverse transcriptase (hTERT) is overexpressed in cancer cells and associated with malignant tumor progression and poor outcome. We thus sought to determine whether the stress hormone norepinephrine (NE) could induce hTERT expression and subsequently ovarian cancer progression. Unexpectedly, NE induced hTERT transcript and protein expression, and subsequently ovarian cancer cell invasion. Pharmacologic inhibition of β2-adrenergic receptor 2 and protein kinase A, as well as silencing of hypoxia-inducible factor-1α and c-Myc expression, profoundly attenuated NE-induced hTERT expression. Strikingly, stimulation of the cells with NE or ectopic expression of hTERT induced expression of Slug, ovarian cancer cell epithelial-mesenchymal transition (EMT) and invasion. Silencing of hTERT expression abrogated NE-induced ovarian cancer cell invasion, EMT and Slug expression. In addition, silencing of Slug expression significantly inhibited NE- and hTERT-induced ovarian cancer cell EMT and invasion. Moreover, continuous exposure to NE was sufficient to enhance in vivo hTERT expression and metastasis of ovarian cancer cells to the lung. Finally, we provide evidence that hTERT links Src to Slug expression in NE-induced ovarian cancer EMT and metastasis. We thus demonstrate a novel role of hTERT in stress hormone-induced ovarian cancer aggressiveness through inducing Slug, providing novel biomarkers and potential therapeutic targets for ovarian cancer.

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

“…In addition, our previous study showed that NE induces ovarian cancer cell EMT through upregulating Slug expression (Choi et al 2015). We therefore determined whether REV inhibits NE-induced ovarian cancer cell EMT.…”

“…1a). Given that chronic stress hormone NE is associated with tumorigenecity and ovarian cancer progression (Nilsson et al 2007;Shahzad et al 2010;Armaiz-Pena et al 2013;Choi et al 2015), we next examined the effect of REV on NE-induced ovarian cancer cell invasion. Stimulation of the cells with NE strongly increased ovarian cancer cell invasiveness (Fig.…”

“…Lysates were resolved by 8 % SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membrane as described previously (Choi et al 2015). The membranes were blocked with 5 % nonfat dried milk in TBST and incubated for 1 h and then probed with the indicated primary antibodies.…”

“…Fixed cells were prepared as described (Choi et al 2015). Immunofluorescence was carried out with anti-E-cadherin (1:100) and Slug (1:100) for overnight.…”

“…Accumulating data show that chronic stress and other behavioral conditions increase catecholamine production and are associated with health outcomes including cancer proliferation and metastasis (McEwen 2002;Lutgendorf et al 2003;Sood et al 2006 showed that behavioral stress (Hassan et al 2013) and stress hormone NE (Lang et al 2004;Choi et al 2015) augments cancer cell progression through b-2 adrenergic receptor (ADBR2). Recently, we have shown that NE induces human telomerase reverse transcriptase (hTERT) and subsequently increases slug expression and ovarian cancer cell invasion (Choi et al 2015), suggesting a new pivotal role of hTERT in stress-induced cancer progression and significance of intervention of signaling pathways for hTERT expression for ovarian cancer patients.…”