Tags

Type your tag names separated by a space and hit enter

Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma.
Cancers (Basel) 2019; 11(7)C

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.

Authors+Show Affiliations

Department of Biotechnology, College of Engineering, Daegu University, Gyeongsan, Gyeongbuk 38453, Korea.Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea. hglee@kribb.re.kr. Department of Biomolecular Science, University of Science and Technology (UST), Daejeon 34141, Korea. hglee@kribb.re.kr.Department of Biotechnology, College of Engineering, Daegu University, Gyeongsan, Gyeongbuk 38453, Korea. sckang@daegu.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31311167

Citation

Singh, Mahendra Pal, et al. "Morin Hydrate Reverses Cisplatin Resistance By Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma." Cancers, vol. 11, no. 7, 2019.
Singh MP, Cho HJ, Kim JT, et al. Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma. Cancers (Basel). 2019;11(7).
Singh, M. P., Cho, H. J., Kim, J. T., Baek, K. E., Lee, H. G., & Kang, S. C. (2019). Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma. Cancers, 11(7), doi:10.3390/cancers11070986.
Singh MP, et al. Morin Hydrate Reverses Cisplatin Resistance By Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma. Cancers (Basel). 2019 Jul 15;11(7) PubMed PMID: 31311167.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma. AU - Singh,Mahendra Pal, AU - Cho,Hee Jun, AU - Kim,Jong-Tae, AU - Baek,Kyoung Eun, AU - Lee,Hee Gu, AU - Kang,Sun Chul, Y1 - 2019/07/15/ PY - 2019/05/28/received PY - 2019/07/05/revised PY - 2019/07/12/accepted PY - 2019/7/18/entrez KW - Morin hydrate KW - PARP1 KW - autophagy KW - chemoresistance KW - cisplatin KW - hepatocellular carcinoma JF - Cancers JO - Cancers (Basel) VL - 11 IS - 7 N2 - 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. SN - 2072-6694 UR - https://www.unboundmedicine.com/medline/citation/31311167/Morin_Hydrate_Reverses_Cisplatin_Resistance_by_Impairing_PARP1/HMGB1-Dependent_Autophagy_in_Hepatocellular_Carcinoma L2 - http://www.mdpi.com/resolver?pii=cancers11070986 DB - PRIME DP - Unbound Medicine ER -