Abstract
Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC. Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis. Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy-specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy. Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading causes of cancerrelated mortality [1]
Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in hepatocellular carcinoma (HCC) cells
Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading causes of cancerrelated mortality [1]. Surgery is the form of treatment that offers the greatest potential for cure, but most patients have unresectable disease at presentation. With the development of regional cancer therapy and multimodality treatments, localized unresectable large HCCs have been converted to resectable small HCCs [3]. Locoregional chemotherapy, such as hepatic arterial infusion chemotherapy, is commonly used as a nonsurgical approach for downstaging; it does not have the desired effect in most treated HCCs. residual tumor cells after chemotherapy may have a more aggressive behavior that promotes metastasis [4]. Even in patients who undergo radical resection, a majority develop recurrent disease by 5 years [5]. There is an urgent need for improved antitumor drugs for advanced or recurrent HCC
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