Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways

Abstract

Recent reports have confirmed highest levels of growth hormone (GH) receptor (GHR) transcripts in melanoma, one of the most aggressive forms of human cancer. Yet the mechanism of GH action in melanoma remains mostly unknown. Here, using human malignant melanoma cells, we examined the effects of GH excess or siRNA mediated GHR knock-down (GHRKD) on tumor proliferation, migration and invasion. GH promoted melanoma progression while GHRKD attenuated the same. Western blot analysis revealed drastic modulation of multiple oncogenic signaling pathways (JAK2, STAT1, STAT3, STAT5, AKT, mTOR, SRC and ERK1/2) following addition of GH or GHRKD. Further, we show that GH excess upregulates expression of markers of epithelial mesenchymal transition in human melanoma, while the effects were reversed by GHRKD. Interestingly, we observed consistent expression of GH transcript in the melanoma cells as well as marked modulation of the IGF receptors and binding proteins (IGF1R, IGF2R, IR, IGFBP2, IGFBP3) and the oncogenic HGF-MET mRNA, in response to excess GH or GHRKD. Our study thus identifies the mechanistic model of GH-GHR action in human melanoma and validates it as an important pharmacological target of intervention.

The effects of growth hormone on therapy resistance in cancer

“…Autocrine/paracrine GH was further found to turn on EMT cascade in human colorectal cancer cells, where E-cadherin was suppressed with a concomitant increase in mesenchymal proteins Vimentin and FN1, via ERK1/2 [131] ; while exogenously added GH increased Snail and Twist2 and suppressed PTEN activity [96] . We had reported an increase in mesenchymal proteins N-cadherin and Vimentin and decrease of E-cadherin following a GH dose-dependence in human melanoma [132] . Blocking GH signaling by siRNA-mediated GHR knock-down (GHRKD) reversed the effects [132] .…”

“…We had reported an increase in mesenchymal proteins N-cadherin and Vimentin and decrease of E-cadherin following a GH dose-dependence in human melanoma [132] . Blocking GH signaling by siRNA-mediated GHR knock-down (GHRKD) reversed the effects [132] . Consistent results of GH induced EMT were also observed in GHR-expressing pancreatic ductal adenocarcinoma cells following exogenous GH treatment or GHRKD [107] .…”

“…Further, protection of endocrine-resistant breast cancer from ruxolitinib, a JAK2-inhibitor, was reported to coincide with GHR expression [147] . The first clue that GH acts via direct upregulation of ABC-transporter expression in conferring this chemoresistance in tumors came from our study in human melanoma [2,132,148] . We observed that doxorubicin, cisplatin, paclitaxel, oridonin, and vemurafenib, in four different human melanoma cell lines, in presence of GH differentially upregulated ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, ABCG1, and ABCG2 multi-drug efflux pump expressions.…”

Excess growth hormone suppresses DNA damage repair in epithelial cells

“…By contrast, abrogated GH signaling is associated with decreased cancer development in humans and in mice (20,(28)(29)(30). For example, short-stature humans harboring an inactivating mutation in the GH receptor (GHR) do not develop cancer (28), and GHR knockdown in human melanoma cells attenuates tumor progression (31).…”

Growth hormone in the tumor microenvironment

“…GH and GHR are abundantly expressed in human melanoma cells, and treatment with GH resulted in decreased E cadherin and increased N cadherin, while GHR knockdown reversed the effect (60). Conversely, silencing GH signaling in human pancreatic ductal adenocarcinoma cell lines resulted in increased E cadherin, while EMT markers including N cadherin, Zeb, Snail, and Slug were suppressed (61).…”