Abstract
Renal cell carcinoma (RCC), the most common malignancy of the kidney, is refractory to standard therapy and has an incidence that continues to rise. Screening of plant extracts in search of new agents to treat RCC resulted in the discovery of englerin A (EA), a natural product exhibiting potent selective cytotoxicity against renal cancer cells. Despite the establishment of synthetic routes to the synthesis of EA, very little is known about its mechanism of action. The results of the current study demonstrate for the first time that EA induces apoptosis in A498 renal cancer cells in addition to necrosis. The induction of apoptosis by EA required at least 24 h and was caspase independent. In addition, EA induced increased levels of autophagic vesicles in A498 cells which could be inhibited by nonessential amino acids (NEAA), known inhibitors of autophagy. Interestingly, inhibition of autophagy by NEAA did not diminish cell death suggesting that autophagy is not a cell death mechanism and likely represents a cell survival mechanism which ultimately fails. Apart from cell death, our results demonstrated that cells treated with EA accumulated in the G2 phase of the cell cycle indicating a block in G2/M transition. Moreover, our results determined that EA inhibited the activation of both AKT and ERK, kinases which are activated in cancer and implicated in unrestricted cell proliferation and induction of autophagy. The phosphorylation status of the cellular energy sensor, AMPK, appeared unaffected by EA. The high renal cancer selectivity of EA combined with its ability to induce multiple mechanisms of cell death while inhibiting pathways driving cell proliferation, suggest that EA is a highly unique agent with great potential as a therapeutic lead for the treatment of RCC.
Highlights
Renal cell carcinoma (RCC) is the most common type of malignant kidney tumor with an incidence that continues to rise
As well as to determine the cell death mechanism(s) involved in englerin A (EA)-induced cell death, apoptosis was determined by measuring histone-associated DNA fragments by ELISA in A498 cells treated with 100 nM EA for 24 and 45 h (Figure 1B)
Our results indicated that EA induced cell death in A498 cells, the majority of which, occurred after 24 h of treatment, and at least part of this cell death was due to apoptosis
Summary
Renal cell carcinoma (RCC) is the most common type of malignant kidney tumor with an incidence that continues to rise. Surgery can be curative for tumors confined to the kidney, about 25% of patients have metastatic disease at diagnosis, and another 20-40% develop metastases following surgery [2,3]. The VHL gene product is involved in oxygen and energy sensing by regulating the activity of the hypoxia inducible factors (HIFs) [8]. Inactivation of VHL results in HIF stabilization and the activation of transcription of over 60 hypoxiaresponsive genes involved in oncogenesis and tumor progression including vascular endothelial growth factor (VEGF), the platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF-α), epidermal growth factor (EGF), and glucose transporter-1 (GLUT-1)
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