Neha Arora

Introduction. Melanoma has been one of the fastest growing cancers over the last 50 years in the United States.¹ The most common mutation in melanoma is of the BRAF gene which causes constitutive activation of the MAP kinase pathway, leading to uncontrolled cell proliferation. About 15-20% of melanoma patients don’t respond to traditional BRAF and immune checkpoint inhibitors due to either primary resistance or developed resistance over time.² In cases where surgical excision is not possible or melanoma has progressed through metastasis, this can lead to delays in effective treatment. Hypoxic conditions present in these tumors activate the HIF-1a transcription factor, which is responsible for increasing tumor aggressiveness, metastasis, and drug therapy failure.³ Targeting HIF-1a through this pathway has the potential to provide a therapeutic response for drug-resistant or non-responsive melanoma patients. Methods. Preexisting melanoma cell lines were used to assess response both in culture and in vivo. Tumor cells were grown in the presence of cobalt chloride to mimic hypoxic conditions and HIF-1a inhibitors such as cinnamaldehyde, simvastatin, and luteolin were administered.^4,5,6 Levels of HIF-1a and tumorigenic proteins were analyzed using Western Blot and qRT-PCR.^4,5,6 Melanoma cells were also grown and transplanted into mice, with certain groups receiving either a saline or oral HIF-1a inhibitor treatment.⁴ Virus encoding miRNA-138 vector, a sequence known to downregulate HIF-1a, was infected into melanoma cells later transplanted in mice.⁷ Results. GLUT-1 expression was analyzed using western blotting after administration of HIF-1a inhibitor in three different melanoma cell line cultures.⁸ In comparison to control actin, GLUT-1 was significantly downregulated in cells following treatment with ACF.⁸ Lung weight was analyzed to determine metastasis in miRNA administered mice and found to be significantly decreased in comparison to control.⁷ Epithelial to mesenchymal transition (EMT) was assessed using E-cadherin, N-cadherin, and vimentin markers.⁶ E-cadherin was increased while N-cadherin and vimentin were decreased in melanoma cells cultured with HIF-1a inhibitor.⁶ Conclusion. Hypoxic conditions activate increased expression of HIF-1a, which subsequently increases survival of melanoma tumor cells. This can be through upregulation of GLUT-1 to improve growth and metabolic processing. It can also be through promoting metastasis and increasing EMT, both of which ultimately increase disease burden. Targeting expression of HIF-1a has significant potential as a therapy for drug-resistant melanoma patients.

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