Abstract
Chemoresistance is a major obstacle that limits the benefits of cisplatin-based chemotherapy in various cancers, including hepatocellular carcinoma. De-regulation of the poly(ADP-ribose) polymerase 1 (PARP1)/high-mobility group box 1 (HMGB1) signaling pathway has been proposed as an important mechanism involved in cisplatin-resistance. In this study, we investigated therapeutic potential of a natural flavonoid Morin hydrate against cisplatin-induced toxicity using the HepG2DR multi-drug resistant cell line, which is derived from the HepG2 human hepatocellular carcinoma cell line. HepG2DR cells were exposed to cisplatin and Morin hydrate alone or together after which autophagy and apoptotic signaling pathways were monitored by fluorometric assay and Western blot analysis. Xenograft mouse models were performed to confirm the in vitro effect of Morin hydrate. PARP1 was hyper activated in cisplatin-resistant HepG2DR cells. Cisplatin-induced PARP1 activation resulted in chemoresistance via increased autophagy. The cisplatin/Morin hydrate combination was effective in the reversal of the HepG2DR cell resistance via suppression of PARP1-mediated autophagy by regulating the HMGB1 and microtubule-associated protein 1A/1B light chain 3B (LC3) I/II. Moreover, PARP1 inhibition by 4-amino-1,8-naphthalimide or autophagy inhibition by a knockdown of the autophagy-related 5 (ATG5) gene resulted in sensitizing the HepG2DR cells to cisplatin (CP) through activation of the c-Jun N-terminal kinase (JNK) pathway. In a mouse xenograft model, the treatment of cisplatin with Morin hydrate reversed the increased expression of PARP and HMGB1 and significantly suppressed tumor growth. These findings indicate dysregulated expression of PARP1 confers cisplatin-resistance via autophagy activation in HepG2DR cells. Morin hydrate inhibits cisplatin-mediated autophagy induction, resulting in increased susceptibility of HepG2DR cells to cisplatin cytotoxicity. The combination of Morin hydrate with cisplatin may be a promising therapeutic strategy to enhance the efficacy of conventional chemotherapeutic drugs.
Highlights
Hepatocellular carcinoma (HCC) accounts for approximately 80–90% of liver cancers and is the second leading cause of cancer deaths globally [1]
The expression of p62 significantly increased in HepG2DR cells after CP-ethyl pyruvate (EP) and CP-Morin hydrate (MH) treatments, compared with that in EP-treated HepG2DR cells and in untreated HepG2WT cells (Figure 3E). These results suggest that CP-induced poly(ADP-ribose) polymerase 1 (PARP1) expression and cytoplasmic translocation of high-mobility group box 1 (HMGB1) appear to be the major causes of the development of CP resistance in HepG2DR cells via autophagy activation
The results showed a significant reduction in the expression levels of the PARP1, HMGB1, and LC3I/II proteins and a significant increase in the expression level of cleaved caspase-3 after CP-MH treatment compared with those in the vehicle-treated groups (Figure 7E)
Summary
Hepatocellular carcinoma (HCC) accounts for approximately 80–90% of liver cancers and is the second leading cause of cancer deaths globally [1]. Cancers 2019, 11, 986 and poor survival benefits because of the development of multidrug resistance [3]. The mechanism of chemoresistance is not fully understood, recent evidence has revealed that stress-induced autophagy may contribute in part to the HCC chemoresistance [4]. A number of stress-inducing factors promote the activation of autophagy, including nutrient deficiency, a high temperature or pH, and chemical treatment. The pro-survival role of autophagy contributes to cytoprotective events, which help cells develop chemoresistance, while its pro-death role results in cancer cell death [7]. A recent study has implicated poly(ADP-ribose) polymerase 1 (PARP1)
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