In recent years, several approved small-molecule kinase inhibitors have been shown to prolong survival of patients with renal cell carcinoma (RCC), but there is still a major need for novel therapies. Turcotte and colleagues now present data indicating that the molecule STF-62247 — identified by screening RCC cells deficient in the von Hippel–Lindau (VHL) tumour suppressor gene, which is inactive in 75% of patients with RCC — induces cytotoxicity and reduces RCC growth through autophagy.
To identify STF-62247, the authors screened 64,000 compounds against wild-type VHL and VHL-deficient RCC cells. STF-62247 was shown to be selectively toxic to VHL-deficient cells compared with wild-type cells. Next, using VHL-null RCC4 cells expressing short-hairpin RNA against the VHL-regulated genes hypoxia-inducible factor 1α (HIF1α) and HIF2α, they showed that reduced expression of HIF1α or HIF2α did not affect cell death induced by STF-62247. Previously HIF2α has been shown to be crucial for tumour growth in RCC but this result indicated that cytotoxicity in VHL-null cells induced by STF-62247 is independent of HIF.
To test the effect of STF-62247 on tumour growth in vivo, VHL-deficient RCC tumours were implanted into immunodeficient mice. Daily treatment with STF-62247 induced a concentration-dependent decrease in VHL-deficient tumour growth but had no effect on wild-type VHL tumours.
In vitro studies investigating the mechanism of action showed that STF-62247 does not induce apoptosis or change the phosphorylation or total levels of p53 in VHL-deficient cells, suggesting that the molecule does not act via a DNA damage signalling pathway. However, the cells accumulated intracytoplasmic vacuoles characteristic of cells undergoing autophagy. This was confirmed by detecting the lipidated form of the microtubule-associated protein light chain 3 found in cells undergoing autophagy in an STF-66247 concentration-dependent manner.
Several studies indicated that STF-66247 targets the trans-Golgi network (TGN): brefeldin A, a blocker of protein transport from the endoplasmic reticulum to the Golgi apparatus, abolished the formation of autophagic vacuoles in STF-62247-treated VHL-deficient cells. Also, a screen of a yeast deletion pool showed that cells lacking proteins involved in Golgi trafficking and in morphogenesis were more sensitive to STF-62247. Moreover, small interfering RNA knockdown of three proteins involved in the trans-Golgi network — ALG5, OSBPL3 and CHMP6 — correlated with VHL status and increased vacuole formation in response to STF-62247.
Overall, STF-62247 induces autophagy — a process that has been implicated in a number of diseases including neuronal degeneration, infectious disease and cancer — in a HIF-independent manner by targeting the TGN, and presents a new opportunity for developing targeted treatments for VHL-deficient RCC.
References
ORIGINAL RESEARCH PAPER
Turcotte, S. et al. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14, 90–102 (2008)
FURTHER READING
Rubinsztein, D. C. et al. Potential therapeutic applications of autophagy. Nature Rev. Drug Discov. 6, 304–312 (2007)
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Hughes, B. Autophagy targeted in kidney cancer. Nat Rev Drug Discov 7, 731 (2008). https://doi.org/10.1038/nrd2674
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DOI: https://doi.org/10.1038/nrd2674
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