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Sonic hedgehog protects endometrial hyperplasial cells against oxidative stress via suppressing mitochondrial fission protein dynamin-like GTPase (Drp1).
Free Radic Biol Med. 2018 12; 129:582-599.FR

Abstract

Hh/Gli1 cascade as well as Gsk3β-Gli1 crosstalk play crucial role in estrogen-dependent progression of endometrial hyperplasia (EH). However, the underlying mechanisms involved in progression of disease still remain unclear. In the present study, we explored the role of Hh signaling in protection of endometrial hyperplasial cells against oxidative stress and the underlying mechanism involved therein. EH cells were found to be more resistant towards H2O2-induced oxidative stress (IC50: ~ 3×) as compared with normal endometrial cells. Estrogen (E2) pre-treatment followed by cytotoxic dose of H2O2, almost rescued the EH cells from apoptosis and caused the increased expression of downstream Shh signaling molecules i.e., Smo, Ptch and Gli1. Whereas pretreatment with cyclopamine was not able to curtail H2O2-induced effects indicating that estrogen protects these cells via activation of Shh pathway. Further, H2O2-induced ROS and lipid peroxidation alongwith decreased activities of antioxidant enzymes glutathione peroxidase and superoxide dismutase were found to be reversed in EH cells pre-exposed to E2 or rShh. The rShh suppressed H2O2-induced cell death and caused attenuation of mitochondrial apoptotic mediators and prevented disruption in mitochondrial morphology and mitochondrial membrane potential in EH cells. The functional blockage of signaling by Shh siRNA or Gli1siRNA led to significantly increased expression of mitochondrial fission protein dynamin-like GTPase (Drp1). The H2O2-treated EH cells showed diminished Gli1 and increased Drp1 expression, concurrent with reduced p-Drp1-(serine637). Whereas rShh pre-treated EH cells presented normal mitochondrial dynamics with dense, long networks of mitochondria alongwith nuclear accumulation of Gli1 and the decreased expression of Drp1. Overall, our results implicated that Shh signaling modulates antioxidant defense system and stabilizes mitochondrial dynamics by suppressing Drp1 protein which maintains survival of EH cells against oxidative stress.

Authors+Show Affiliations

Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow 226031, U.P., India.Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.Department of Obstetrics & Gynaecology, King George's Medical University, Lucknow 226003, U.P., India.Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow 226031, U.P., India.Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow 226031, U.P., India. Electronic address: anila_dwivedi@cdri.res.in.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30347228

Citation

Kaushal, Jyoti B., et al. "Sonic Hedgehog Protects Endometrial Hyperplasial Cells Against Oxidative Stress Via Suppressing Mitochondrial Fission Protein Dynamin-like GTPase (Drp1)." Free Radical Biology & Medicine, vol. 129, 2018, pp. 582-599.
Kaushal JB, Popli P, Sankhwar P, et al. Sonic hedgehog protects endometrial hyperplasial cells against oxidative stress via suppressing mitochondrial fission protein dynamin-like GTPase (Drp1). Free Radic Biol Med. 2018;129:582-599.
Kaushal, J. B., Popli, P., Sankhwar, P., Shukla, V., & Dwivedi, A. (2018). Sonic hedgehog protects endometrial hyperplasial cells against oxidative stress via suppressing mitochondrial fission protein dynamin-like GTPase (Drp1). Free Radical Biology & Medicine, 129, 582-599. https://doi.org/10.1016/j.freeradbiomed.2018.10.427
Kaushal JB, et al. Sonic Hedgehog Protects Endometrial Hyperplasial Cells Against Oxidative Stress Via Suppressing Mitochondrial Fission Protein Dynamin-like GTPase (Drp1). Free Radic Biol Med. 2018;129:582-599. PubMed PMID: 30347228.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sonic hedgehog protects endometrial hyperplasial cells against oxidative stress via suppressing mitochondrial fission protein dynamin-like GTPase (Drp1). AU - Kaushal,Jyoti B, AU - Popli,Pooja, AU - Sankhwar,Pushplata, AU - Shukla,Vinay, AU - Dwivedi,Anila, Y1 - 2018/10/19/ PY - 2018/06/13/received PY - 2018/10/12/revised PY - 2018/10/14/accepted PY - 2018/10/23/pubmed PY - 2019/9/29/medline PY - 2018/10/23/entrez KW - Dynamin-like GTPase KW - Endometrial hyperplasia KW - Estrogen KW - Mitochondrial dynamics KW - Shh signaling SP - 582 EP - 599 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 129 N2 - Hh/Gli1 cascade as well as Gsk3β-Gli1 crosstalk play crucial role in estrogen-dependent progression of endometrial hyperplasia (EH). However, the underlying mechanisms involved in progression of disease still remain unclear. In the present study, we explored the role of Hh signaling in protection of endometrial hyperplasial cells against oxidative stress and the underlying mechanism involved therein. EH cells were found to be more resistant towards H2O2-induced oxidative stress (IC50: ~ 3×) as compared with normal endometrial cells. Estrogen (E2) pre-treatment followed by cytotoxic dose of H2O2, almost rescued the EH cells from apoptosis and caused the increased expression of downstream Shh signaling molecules i.e., Smo, Ptch and Gli1. Whereas pretreatment with cyclopamine was not able to curtail H2O2-induced effects indicating that estrogen protects these cells via activation of Shh pathway. Further, H2O2-induced ROS and lipid peroxidation alongwith decreased activities of antioxidant enzymes glutathione peroxidase and superoxide dismutase were found to be reversed in EH cells pre-exposed to E2 or rShh. The rShh suppressed H2O2-induced cell death and caused attenuation of mitochondrial apoptotic mediators and prevented disruption in mitochondrial morphology and mitochondrial membrane potential in EH cells. The functional blockage of signaling by Shh siRNA or Gli1siRNA led to significantly increased expression of mitochondrial fission protein dynamin-like GTPase (Drp1). The H2O2-treated EH cells showed diminished Gli1 and increased Drp1 expression, concurrent with reduced p-Drp1-(serine637). Whereas rShh pre-treated EH cells presented normal mitochondrial dynamics with dense, long networks of mitochondria alongwith nuclear accumulation of Gli1 and the decreased expression of Drp1. Overall, our results implicated that Shh signaling modulates antioxidant defense system and stabilizes mitochondrial dynamics by suppressing Drp1 protein which maintains survival of EH cells against oxidative stress. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/30347228/Sonic_hedgehog_protects_endometrial_hyperplasial_cells_against_oxidative_stress_via_suppressing_mitochondrial_fission_protein_dynamin_like_GTPase__Drp1__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(18)31046-3 DB - PRIME DP - Unbound Medicine ER -