Abstract
Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ’s inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.
Highlights
Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC representing about 85% of all RCC tumors
We have documented that KTZ effectively and reproducibly inhibits exosome biogenesis in a dose dependent fashion lines[13]
Exosome biogenesis is initiated within the endosomal system and the endosomal sorting complex required for transport (ESCRT) machinery is important for the process of endosomal membrane invagination
Summary
Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. There are no drugs that selectively target pathways involved in exosome biogenesis and secretion by cancer cells and their uptake by recipient cells. Ketoconazole is an FDA approved anti-fungal medication which we have shown to inhibit pathways of exosomal biogenesis and s ecretion[13] Based on those preliminary studies, we examined the mechanism and effect of ketoconazole on biogenesis and secretion of exosome in several RCC cell lines along
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