Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma

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.

Regulation of Rho GTPases by RhoGDIs in Human Cancers

“…Moreover, lymph node metastasis-positive gastric tumors have higher levels of RhoGDI2 expression than lymph node metastasis-negative tumors [80]. RhoGDI2 also protects gastric cancer cells from various chemotherapeutic agents, such as etoposide, staurosporine, and cisplatin, through upregulation of Bcl-2 expression [81,82]. Although RhoGDI1 is completely resistant to degradation during apoptosis, RhoGDI2 is well-characterized as a substrate for caspases and cleaved during apoptosis in various cells [72].…”

Roles of HMGB1 in regulating myeloid-derived suppressor cells in the tumor microenvironment

“…Most studies have revealed that HMGB1 is an inducer for tumor cell autophagy and promotes tumor cell survival through autophagy [58][59][60][61]. Although the influence of autophagy on tumor cell survival has been well characterized, the link between MDSCs and autophagy remains poorly understood.…”

Morin exerts anti-metastatic, anti-proliferative and anti-adhesive effect in ovarian cancer cells: an in vitro studies

“…The presence of two aromatic rings connected by a c-pyrone ring, in which polar hydroxyl groups are bound at various positions to characterize the chemical structure of morin. All hydroxyl groups are responsible for the free radical-scavenging properties of flavonoids [18]. Morin has a promising anti-cancerous activity by reducing DNA damage and modulating signaling pathways responsible for proliferation and differentiation, which could lead to cell-cycle arrest and apoptosis [19,20].…”