Abstract
Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy.
Highlights
Liver cancer, especially hepatocellular carcinoma (HCC), is one of the most common human malignancies and the third leading cause of cancer death worldwide with 600,000 deaths per year [1]
MLN4924 inhibited the growth of liver cancer cells To evaluate the efficacy of MLN4924 on liver cancer cells, Huh-7 cells carrying mutated and inactivated p53 and Hep G2 cells expressing wild-type and functional p53 were treated with MLN4924 and subjected to cell growth analysis
Having established that MLN4924 suppressed the growth of liver cancer cells by modulating autophagy and apoptosis in vitro, we evaluated the in vivo antitumor activity of MLN4924 and elucidated potential mechanisms
Summary
Especially hepatocellular carcinoma (HCC), is one of the most common human malignancies and the third leading cause of cancer death worldwide with 600,000 deaths per year [1]. Liver cancer is annually diagnosed in more than half a million people worldwide. Surgical resection and liver transplantation, in combination with che-. Motherapies when necessary, represent curative treatments for early or localized disease, approximately 80% of patients with liver cancer with advanced disease are not permissible to surgical resection or transplantation and have to mainly rely on traditional chemotherapies [2]. The current chemotherapy is far from satisfaction due to relatively low anticancer efficacy, severe treatment-associated adverse effects, as well as acquired drug resistance, leading to high risk of tumor recurrence and poor long-term survival. The dilemma makes an urgent necessity to identify novel anticancer targets and develop new therapeutic agents with efficient and selective anticancer efficacy to improve the treatment of liver cancer
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