Abstract
Transarterial embolization/transarterial chemoembolization (TAE/TACE) is the acceptable palliative treatment for hepatocellular carcinoma (HCC), mainly through ischemic necrosis induced by arterial embolization. However, how HCC cells survive under such ischemic hypoxic condition remains unclear, which can be exploited to potentiate TAE/TACE treatment. We hypothesized that targeting mitophagy can increase HCC cell apoptosis during hypoxia. HCC cells were subjected to hypoxia and then mitophagy was quantified. The role of dynamin-related protein 1 (DRP1) in hypoxia-induced HCC mitophagy was determined. Moreover, the synergistic effect of hypoxia and DRP1 inhibitor on HCC apoptosis was assessed in vitro and in vivo. Clinical association between DRP1 expression and outcome for HCC patients was validated. HCC cells that survived hypoxia showed significantly increased DRP1-mediated mitochondrial fission and mitophagy compared with cells in normoxia. Hypoxia induced mitophagy in surviving HCC cells by enhancing DRP1 expression and its translocation into the mitochondria and excessive mitochondrial fission into fragments. Blocking the DRP1 heightened the possibility of hypoxic cytotoxicity to HCC cells due to impaired mitophagy and increased the mitochondrial apoptosis, which involved decreased in mitochondrial membrane potential and mitochondrial release of apoptosis-inducing factor and cytochrome c. Additionally, DRP1 inhibitor Mdivi-1 suppressed the in vivo growth of hypoxia-exposed HCC cells. High expression of DRP1 was significantly associated with shorter survival in HCC patients. In conclusion, our results demonstrate that blocking DRP1-mediated mitochondrial fission and mitophagy increases the incidence of mitochondrial apoptosis of HCC cells during hypoxia, suggesting the new approach of targeting mitophagy to potentiate TAE/TACE.
Highlights
In 2018, hepatocellular carcinoma (HCC) was identified as the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide, accounting for ~841,000 new cases and 782,000 deaths[1,2]
This study showed the following details: (i) HCC cells survived hypoxia with a significant increase in DRP1mediated mitochondrial fission and mitophagy. (ii) Blocking dynamin-related protein 1 (DRP1) enhanced cytotoxic hypoxia to HCC cells by impairing mitophagy and increasing mitochondrial apoptosis, which included the decrease in mitochondrial membrane potential and mitochondrial release of apoptosis-inducing factor (AIF) and cytochrome c. (iii) DRP1 inhibitor Mdivi-1 suppressed the in vivo growth of hypoxia-surviving HCC cells. (iv) DRP1 was highly expressed in HCC tissues, predictive of a poor prognosis of patients
The fluorescent staining of the outer mitochondrial membrane 20 (TOM20) or Mito Tracker Green was weaker whereas the intensity of Lyso Tracker Red was stronger in HCC cells subjected to hypoxia, indicating that an accelerated mitochondrial degradation by lysosomes is triggered during the adaption of HCC cells to hypoxia, leading to the decrease of mitochondrial mass
Summary
In 2018, hepatocellular carcinoma (HCC) was identified as the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide, accounting for ~841,000 new cases and 782,000 deaths[1,2]. Lin et al Oncogenesis (2020)9:67 can extend survival, but the incidence of local tumor recurrence is relatively high. In excised HCC specimens, peripheral residuals of viable tumor cells are common after TAE/TACE, which may contribute to local recurrence[7]. Emerging evidences show that HCC cells capable of surviving TAE/TACE obtain a more invasive phenotype[8]. How HCC cells develop an adaptation to survive the ischemic hypoxia induced by TAE/TACE is unclear. This could be analyzed to enhance the embolic effects of TAE/TACE
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