Akt inhibition attenuates rasfonin-induced autophagy and apoptosis through the glycolytic pathway in renal cancer cells

• Published in: Cell death & disease 2015-12, Vol.6 (12), p.e2005-e2005
• Main Authors: Lu, Q, Yan, S, Sun, H, Wang, W, Li, Y, Yang, X, Jiang, X, Che, Y, Xi, Z
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/31; 13/89; 13/95; 14/19; 14/28; 38/77; 42; 631/67/589/1588; 631/80/82/23; 631/80/82/39; 631/80/86; Antibodies; Apoptosis - drug effects; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Drug Interactions; Fatty Acids, Unsaturated - pharmacology; Glycolysis - drug effects; HeLa Cells; Humans; Immunology; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Life Sciences; Original; original-article; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Pyrones - pharmacology; Transfection
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.344

Rasfonin is a fungal secondary metabolite with demonstrated antitumor effects. However, the underlying mechanism of the regulatory role in autophagy initiated by rasfonin is largely unknown. Moreover, the function of Akt to positively mediate the induced autophagy remains elusive. In the present study, we observed that rasfonin induced autophagy concomitant with the upregulation of Akt phosphorylation. Both the inhibition of Akt by small molecule inhibitors and genetic modification partially reduced rasfonin-dependent autophagic flux and PARP-1 cleavage. The overexpression of myrAkts (constant active form) promoted rasfonin-induced apoptosis and autophagy in a cell type- and Akt isoform-specific manner. Using quantitative PCR and immunoblotting, we observed that rasfonin increased the expression of glycolytic gene PFKFB3 , and this increased expression can be suppressed in the presence of Akt inhibitor. The inhibition of PFKFB3 suppressed rasfonin-activated autophagy with enhanced PARP-1 cleavage. In the case of glucose uptake was disrupted, which mean the glycolytic pathway was fully blocked, the rasfonin-induced autophagy and PARP-1 cleavage were downregulated. Collectively, these results demonstrated that Akt positively regulated rasfonin-enhanced autophagy and caspase-dependent apoptosis primarily through affecting the glycolytic pathway.