Autophagy is the process through which cells recycle proteins and organelles for energy, and is often dysregulated in kidney cancers. A recent study shows that autophagy is increased in FLCN-null renal carcinoma cells, and that these cells are more sensitive to irradiation (IR) than FLCN-expressing counterparts.
Zhang et al. (2014) assessed the survival of a number of different renal cell carcinoma (RCC) cell lines (UOK-257, UOK-257-2, ACHN, 786-O, 769-P and Caki-1), and found that two FLCN-deficient cell lines – UOK-257 and ACHN expressing anti-FLCN siRNAs – showed decreased survival following IR, in a dose-dependent manner. TUNEL assays indicated that this was not due to increased apoptosis in FLCN-deficient cells, thus the researchers investigated whether autophagy was affected in these cells.
Indeed, increased autophagy was observed in FLCN-deficient cells compared to FLCN-expressing cells, and appeared to further increase in irradiated FLCN-null cells, again in a dose-dependent manner. Furthermore, inhibiting autophagy using 3-Methyladenine or anti-Beclin1 siRNAs abrogated the effects of IR on survival only in FLCN-null cells, whilst treatment of cells with Rapamycin, a known autophagy inducer, further increased sensitivity of FLCN-null cells to IR. Together, these results suggest that IR specifically induces autophagic cell death in FLCN-null cells where autophagy is already dysregulated.
Levels of phosphorylated MEK and ERK were increased in FLCN-deficient cells before IR treatment, suggesting that increased MEK-ERK signalling is responsible for autophagy induction in FLCN-null cells. This is not surprising as FLCN has been previously shown to inhibit both autophagy and MEK-ERK signalling (Baba et al., 2008, Bastola et al., 2013, Gaur et al., 2012, Zhang et al., 2013). However, following IR, autophagy was further increased in FLCN-null cells and cell survival decreased.
This suggests that a specific range of autophagic flux allows FLCN-null cells to survive inappropriately and form tumours, but that increasing autophagic flux beyond this range renders cells unviable. Indeed, the same group previously reported that while the chemotherapy, Paclitaxel, induced autophagy and cell death in FLCN-null cells, toxicity was increased when the drug was administered in combination with autophagy inhibitors. In fact, both autophagy activation and inhibition can be tumorigenic (Levine and Kroemer, 2008). Therefore, whether autophagy is qualitatively activated or inhibited may be less important in determining a cell’s tumorigenic potential, than whether the resultant autophagic flux falls within a quantitative window of opportunity.
Radiation therapy is currently used to treat almost 50% of cancer cases, usually in combination with other treatments, and works by causing such extensive DNA damage in cancer cells that they die. Indeed, the fact that FLCN-null cells were more sensitive to IR than FLCN-expressing cells may suggest that FLCN plays some role in DNA damage repair, as do many other tumour suppressor genes. Kidney cancers are usually resistant to radiotherapy and it is rarely used to treat sporadic cases. The results of this study suggest that, due to the different underlying biology of BHD-associated kidney tumours, radiotherapy may actually be a viable treatment to specifically target FLCN-null tumour cells. However, as with many cancer treatments, the side-effects of radiotherapy can be severe, meaning that more research will needed before radiotherapy is used to treat BHD patients with kidney cancer.
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- Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, & Czyzyk-Krzeska MF (2013). Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. PloS one, 8 (7) PMID: 23922894
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- Zhang Q, Si S, Schoen S, Chen J, Jin XB, & Wu G (2013). Suppression of autophagy enhances preferential toxicity of paclitaxel to folliculin-deficient renal cancer cells. Journal of experimental & clinical cancer research : CR, 32 (1) PMID: 24305604
- Zhang Q, Si S, Schoen S, Jin XB, Chen J, & Wu G (2014). Folliculin-deficient renal cancer cells exhibit higher radiosensitivity through autophagic cell death. The Journal of urology PMID: 24434776
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