Abstract
Melanoma, an extremely drug resistant form of cancer, displays elevated levels of growth hormone (GH) and growth hormone receptor (GHR) expression. We have described a GH dependent mechanism of chemoresistance in melanoma through a series of earlier studies. In GHR overexpressing human melanoma, GH action drives active drug efflux and phenotype switching by upregulating ATP-binding cassette transporters (ABC-transporters) and epithelial-to-mesenchymal transition (EMT) markers. Inhibition of GHR activation reverses these effects, increases drug retention, and sensitizes the melanoma cells to chemotherapy. GH action in melanoma also appears to drive drug sequestration in melanosomes as we present here. GH action was found to modulate the levels of melanocyte-inducing transcription factor (MITF), the master regulator of melanosome synthesis and melanoma. Additionally, MITF target gene levels and drug sequestering ABC transporter expression were also elevated by GH treatment in vitro and in vivo in mouse tumor xenografts. This was corroborated by in silico analyses of tumor databases. Furthermore, we observed a dose dependent increase in tyrosinase activity and melanogenesis in human melanoma cells with GH, in the presence of chemotherapy, which was suppressed by siRNA mediated GHR inhibition. Thus, we describe an array of molecular mechanisms by which GH drives chemoresistance in melanoma. Therefore, GHR inhibition combined with chemotherapy should lead to better tumor clearance and improve overall survival.
Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways
