Growth hormone signal transduction in primary metastatic melanoma cell lines: a potential therapeutic target

Abstract

Melanoma is considered to be the most dangerous form of skin cancer and is responsible for 80% of skin-cancer related mortality. The progression of the disease is very complex, involving activation of many signalling pathways which, in turn, enhances the potential of the tumour to evolve and become metastatic. One of the biggest challenges in treating this disease is the development of drug resistance. A better understanding of the molecular mechanisms involved in the progression of the disease and discovery of new targeted therapies has the potential to prolong survival and lead to improved treatment strategies and better outcomes for patients. A large body of evidence implicates the growth hormone (GH)/Insulin-like growth factor 1 (IGF1) axis in multiple cancer types and has led to increasing interest in targeting GH or the GH receptor (GHR) as a therapeutic strategy in cancer. GH signalling has been reported to promote cancer progression in a range of tumour types such as breast, prostate, lung, endometrial and colorectal cancers. Targeting GH signalling may also be a promising avenue for treating melanoma, as previous studies have reported high expression levels of GHR mRNA and protein in commercial melanoma cell lines from the NCI60 panel. The current study aimed to characterise the GH/GHR signalling pathway in melanoma using a panel of human primary melanoma cell lines (NZM) developed at the Auckland Cancer Society Research Centre at The University of Auckland. Thirty NZM cell lines were selected and tested for response to GH, prolactin (PRL) and a specific GHR antagonist, by assessing STAT5 phosphorylation by western blotting. From the panel of melanoma cell lines, 70% of the cell lines responded to GH stimulation, and GHR inhibition, and mRNA expression analysis demonstrated that the GHR was highly expressed across cell lines. Functional analysis demonstrated GH stimulates and promotes cell proliferation and migration in a subset of NZM cell lines and blocking GHR signalling may abrogate this. Lastly, it was demonstrated that GH stimulated tumour growth in a xenograft model of melanoma. Collectively the results from my thesis demonstrate the potential for GH to promote melanoma progression and provide evidence to support that inhibiting GH may be a novel treatment strategy for melanoma.