A CXCR1/CXCR2 and heterologous GPCR antagonism in melanoma development

Abstract

Being the most aggressive human skin cancers, melanoma has always occurred with a poor prognosis. It is responsible for 80% of skin cancer. Treatments for melanoma include surgical removal, and radio- and chemotherapy, which are not effective toward the advanced stages of the disease. Only three chemotherapy drugs, hydroxyurea, dacarbazine and interleukin-2, are currently approved by the Food and Drug Administration for metastatic melanoma, and the therapeutic response rate is only 5%-20%. Thus, there is a need for novel therapies that can target tumours, especially when the tumour cells become refractory to chemotherapy. ELR–CXC chemokines with a Glutamine – leucine – arginine (ELR) motif (for example, interleukin-8/CXCL8) are able to chemoattract neutrophils during inflammation responses via their receptors, CXCR1 and CXCR2, which can be expressed by human malignant tumour cells, keratinocytes, endothelial cells, and fibroblasts. CXCR1 and CXCR2 play very important roles in melanoma by promoting tumour cell proliferation, angiogenesis, and metastasis. They are also involved in the tumour’s becoming refractory to chemotherapy. An ELR–CXC chemokine antagonist developed by our lab, CXCL8(3-72)K11R/G31P (G31P), effectively blocks CXCR1- and CXCR2- induced inflammatory responses, and further antagonizes the functions of heterologous G protein–coupled receptor’s (GPCR). The tumour–associated GPCRs, along with ELR–CXC chemokines and their receptors, have been shown to simultaneously increase in several tumour models, including melanoma. Thus, given the knowledge regarding the importance of the ELR-CXC chemokines and heterologous GPCRs’ in melanoma and G31P’s ability to block ELR-CXC chemokines and at least some heterologous GPCRs, we hypothesize that G31P is a viable therapeutic option for melanoma cancers by virtue of its success in blocking tumour progression in mouse models. Our data indicated that ELR-CXC chemokine antagonism with G31P had no significant impact on tumour growth or tumour-induced angiogenesis, which suggested that blockade of CXCR1 and CXCR2 alone was insufficient to block tumour development in this melanoma mouse model. Evaluation of other tumour-related parameters (e.g., angiogenic patterns and stress protein level) are recommended as a means of determining what parameters beyond CXCR1 and CXCR2 signaling are important in tumour progression in our matrigel model.