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Article Publish Status: FREE
Abstract Title:

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

Abstract Source:

Int J Mol Sci. 2020 Nov 4 ;21(21). Epub 2020 Nov 4. PMID: 33158052

Abstract Author(s):

Mahendra Pal Singh, Tejinder Pal Khaket, Vivek K Bajpai, Saleh Alfarraj, Se-Gie Kim, Lei Chen, Yun Suk Huh, Young-Kyu Han, Sun Chul Kang

Article Affiliation:

Mahendra Pal Singh

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, Cyttranslocation 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.

Study Type : In Vitro Study

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