The most common subtype of renal cell carcinoma (RCC) is the clear cell RCC (ccRCC) that accounts for 70-80% of cases. The fate of ccRCC is linked to alterations of genes that regulate TP53. The dysfunction of p53 affects several processes including autophagy, which is increased in different advanced carcinomas and could be associated with cancer progression. We report that different kidney cancer cell lines show higher levels of autophagy than control cells. The increased autophagy is associated with the upregulation of miR501-5p, which stimulates mTOR-independent autophagy by the activation of AMP kinase. AMPK activation occurs through the decrease of ATP generation caused by the downregulation of the mitochondrial calcium uniporter (MCU) that leads to the reduction of mitochondrial calcium uptake. Autophagy induction promotes the degradation of p53 through the autophagolysosomal machinery. Consistently, the inhibition of autophagy reduces both cell proliferation and migration enhancing the expression of p53, p21 and E-Cadherin as well as decreasing Vimentin synthesis. Taken together, these findings indicate that autophagy is involved in the progression of kidney cancer. Therefore, the pharmacological targeting of this process could be considered an interesting option for the treatment of advanced renal carcinoma.
Experimental cell research. 2020 Jul 24 [Epub ahead of print]
Simone Patergnani, Sonia Guzzo, Alessandra Mangolini, Lucio dell'Atti, Paolo Pinton, Gianluca Aguiari
Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, via Fossato di Mortara 70 c.o. viale Eliporto, 44121, Ferrara, Italy., Department of Biomedical and Surgical Specialty Sciences, University of Ferrara, via Fossato di Mortara 74, 44121, Ferrara, Italy., Institute of Urology, University Hospital "Ospedali Riuniti", via Conca 71, 60126, Ancona, Italy., Department of Biomedical and Surgical Specialty Sciences, University of Ferrara, via Fossato di Mortara 74, 44121, Ferrara, Italy. Electronic address: .