Ischemia may be the most common pathological occurrence to restrict nutrient availability and induce macroautophagy/autophagy. As a self-digestive process, autophagy helps sustain nutrient/energy and restrict damages in short-term scenarios, but it switches to a self-destructive process leading to cell death in long-term scenarios. Notably, ischemia has been used as one clinical application to treat cancer, particularly transarterial embolization (TAE) and chemoembolization (TACE) as the first-line treatments of intermediate-stage hepatocellular carcinoma (HCC, the predominant type of liver cancer). Partly due to the induced autophagy together with hypoxia-induced angiogenesis, TAE/TACE is not successful to treat HCC in many cases. Our recent work demonstrated that simultaneous treatments with sorafenib (a first-line therapeutic agent for advanced HCC) can sensitize HCC cells to cell death induced by glucose starvation via impairing mitophagy, a mitochondria-specific form of autophagy. Moreover, we identified SIAH1 as an important E3 ubiquitin ligase for mitophagic induction in HCC cells.
Keywords: HCC; canagliflozin; glucose restriction; mitophagy; sorafenib.