Autophagy dysregulation is a common feature of hereditary kidney cancer syndromes

Autophagy is an adaptive catabolic process which recycles cellular proteins and organelles to produce energy, allowing cells to survive in stressful conditions, such as hypoxia or starvation.

Autophagy can promote cell survival or apoptosis, and as such both increased and decreased autophagy is able to promote tumorigenesis (Levine and Kroemer, 2008). Enhanced autophagy can allow cancer cells to survive, despite the low oxygen and low nutrient availability often found in tumours; alternatively, decreased autophagy can prevent the activation of autophagic programmed cell death meaning that cancerous cells could survive inappropriately and form tumours. It is becoming increasingly clear that autophagy dysregulation is a common feature of many cancers (Levine and Kroemer, 2008), including hereditary kidney cancer syndromes.

Two recent papers show that the tuberous sclerosis complex gene, TSC2, activates autophagy in response to nitric oxide and reactive oxygen species, which are both cellular damaging agents (Tripathi et al., 2013, Zhang et al., 2013). Autophagy activation in this setting was cytotoxic (Zhang et al., 2013), indicating that in this particular context, the autophagy pathway stimulates apoptosis. Conversely, it has previously been reported that although autophagic flux is low in TSC2-null cells, complete inhibition of autophagy – in combination with mTOR inhibition – significantly reduces tumour formation of TSC2-null cells in xenograft experiments (Parkhitko et al., 2011). Therefore, in these experiments, autophagy stimulates cell survival, indicating that the relationship between autophagy and tumorigenesis in tuberous sclerosis is not straight forward.

In 2008, it was reported that autophagy induction with a small molecule STF-62247, selectively induced cell death in VHL-null RCC cells compared to genetically matched cells with wild type VHL (Turcotte et al., 2008). Counterintuitively, VHL has subsequently been reported to inhibit autophagy (Mikhaylova et al., 2012), indicating that the relationship between VHL and autophagy is not straightforward either.

Studies from the same group recently showed that VHL’s effect on autophagy is partially mediated by FLCN (Bastola et al., 2013) and autophagy is increased in flies lacking the Drosophila FLCN homologue, DBHD (Liu et al., 2013), both suggesting that FLCN inhibits autophagy. Several studies further link FLCN to autophagy: Gharbi et al. found that flcn-1 deficient nematode worms have an increased lifespan, as do worms in which autophagy has been induced (Schiavi et al., 2013). Secondly, the FLCN interactor FNIP1 has been reported to interact with GABARAP, a component of the autophagy pathway (Behrends et al., 2010). Additionally, a number of proteins containing a non-canonical DENN domain similar to FLCN’s function in the autophagy pathway (Zhang et al., 2012)

While it is clear that autophagy is dysregulated in syndromic kidney cancers, quite how this leads to tumorigenesis is not clear cut. The experiments in tuberous sclerosis show that both activating and inhibiting autophagy may prevent tumorigenesis. This could mean that autophagic flux needs to be maintained a specific rate for healthy cell homeostasis, and that deviation in either direction is tumorigeneic. Alternatively, it could be that cellular context determines the relationship between autophagy and tumorigenesis, meaning that outcomes will be different in different cells, or at different stages of disease progression.

It is important to answer these questions, as doing so may shed light on the pathogenic mechanisms of these kidney cancers, and may also suggest therapeutic targets. Additionally, if the role of autophagy changes during disease progression, the recommended treatment may vary depending on whether the patient presents with early or advanced disease. There are a number of FDA approved drugs that modify autophagy (Shu et al., 2012), meaning that these could be rapidly repurposed if proven to be effective treatments for kidney cancer.

 

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www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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