Morin Hydrate Sensitizes Hepatoma Cells and Xenograft Tumor towards Cisplatin by Downregulating PARP-1-HMGB1 Mediated Autophagy

Abstract

The cross-talk between apoptosis and autophagy influences anticancer drug sensitivity and cellular death in various cancer cell lines. However, the fundamental mechanisms behind this phenomenon are still unidentified. We demonstrated anti-cancerous role of cisplatin (CP) and morin hydrate (Mh) as an individual and/or in combination (CP-Mh) in hepatoma cells and tumor model. Exposure of CP resulted in the production of intracellular reactive oxygen species (ROS)-mediated cellular vacuolization, expansion of mitochondria membrane and activation of endoplasmic reticulum (ER)-stress. Consequently, Cyt c translocation led to the increase of Bax/Bcl-2 ratio, which simultaneously triggered caspase-mediated cellular apoptosis. In addition, CP-induced PARP-1 activation led to ADP-ribosylation of HMGB1, which consequently developed autophagy as evident by the LC3I/II ratio. Chemically-induced inhibition of autophagy marked by increased cell death signified a protective role of autophagy against CP treatment. CP-Mh abrogates the PARP-1 expression and significantly reduced HMGB1-cytoplasmic translocation with subsequent inhibition of the HMGB1-Beclin1 complex formation. In the absence of PARP-1, a reduced HMGB1 mediated autophagy was observed followed by induced caspase-dependent apoptosis. To confirm the role of PARP-1-HMGB1 signaling in autophagy, we used the PARP-1 inhibitor, 4-amino-1,8-naphthalimide (ANI), HMGB1 inhibitor, ethyl pyruvate (EP), autophagy inhibitors, 3-methyl adenine (3-MA) and bafilomycin (baf) and small interfering RNAs (siRNA) to target Atg5 in combination of CP and Mh. Exposure to these inhibitors enhanced the sensitivity of HepG2 cells to CP. Collectively, our findings indicate that CP-Mh in combination served as a prominent regulator of autophagy and significant inducer of apoptosis that maintains a homeostatic balance towards HepG2 cells and the subcutaneous tumor model.

Naringenin and morin reduces insulin resistance and endometrial hyperplasia in the rat model of polycystic ovarian syndrome through enhancement of inflammation and autophagic apoptosis

“…The remarkable suppression of adhesion and migration of SKOV-3 and A2780 cell lines together with the distinct regulation of autophagy and significant apoptotic induction was noticed after treatment with morin, although the exact autophagic mechanism of morin is still unknown (Nowak et al, 2020;Pal Singh et al, 2020). Autophagy activation has been implicated in cisplatin resistance, while autophagy suppression improves the effectiveness of morin in SKOV-3 cells (Bieg et al, 2018;Pal Singh et al, 2020). A study found that morin can induce melanoma cell apoptosis with ROS regulating pro and anti-apoptotic proteins (Lee et al, 2019).…”

Inflammatory Caspase Activity Mediates HMGB1 Release and Differentiation in Myoblasts Affected by Peripheral Arterial Disease

“…We showed here that caspase-1 expression was higher in intermittent claudication, but undetectable in densely ischemic tissue affected by critical limb ischemia, which may also reflect similar state of cell exhaustion which is a hallmark of cellular senescence [ 36 ]. Another possible explanation for why HMGB1 release was reduced in ischemic cells is that its translocation is limited [ 37 ]. We showed very prominent nuclear HMGB1 staining in ischemic muscle affected by CLI, which would support this idea [ 38 ].…”

Noncoding RNAs and their therapeutics in paclitaxel chemotherapy: Mechanisms of initiation, progression, and drug sensitivity

“…Migration and proliferation of tumors can be suppressed by the natural compound morin (Nowak et al, 2020). Furthermore, this naturally occurring flavanol compound increased chemosensitivity via inhibition of autophagy (Pal Singh, Pal Khaket, et al, 2020). In prostate cancer cells, morin reduced miRNA‐155 expression to induce the expression of GATA binding protein 3 (GATA3), leading to PTX sensitivity (Li, Jin, et al, 2017).…”