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.
Scientific reports. 2021 May 13*** epublish ***
Jacob W Greenberg, Hogyoung Kim, Ahmed A Moustafa, Amrita Datta, Pedro C Barata, A Hamid Boulares, Asim B Abdel-Mageed, Louis S Krane
Departments of Urology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA., Departments of Urology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA. ., Department of Internal Medicine, Section of Hematology/Oncology, Tulane University School of Medicine, New Orleans, LA, 70012, USA., The Stanley Scott Cancer Center/Louisiana Cancer Research Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA., Departments of Urology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA. .