Morin supplementation modulates PERK branch of UPR and mitigates 1,2-dimethylhydrazine-induced angiogenesis and oxidative stress in the colon of experimental rats

Abstract

Angiogenesis, disturbance in redox homeostasis, and deregulated redox signaling are considered as common hallmarks of cancer progression and chemo resistance. In this context, PERK (protein kinase PKR-like ER kinase) branch of the unfolded protein response (UPR), an adaptive mechanism triggered by endoplasmic reticulum (ER) stress to cope with protein misfolding and perturbed proteostasis, has shown to regulate angiogenesis and oxidative stress. This study aimed to investigate the impact of morin, a poly phenolic compound from the family of Moraceae on PERK–Nrf2–VEGF axis in experimental rats challenged with the colon specific procarcinogen 1,2-dimethylhydrazine (DMH). Male albino Wistar rats were randomized into four groups (n = 6) viz., control, morin control, DMH control, and DMH administered rats treated with morin. Immunohistochemical analysis of colonic cross-section revealed that DMH alone administered rats showed significantly increased expression of Nrf2 predominantly in the cytoplasm. Angiogenic growth factors viz., VEGF, PDGF, and bFGF are also shown to be increased in the DMH alone administered tumor bearing rats as compared to control. Significant downregulation was also observed in the downstream targets of Nrf2 such as hemeoxygenase 1 (HO1), glutathione peroxidase 2 (GPX2), thioredoxin (TRXN), glutathione S transferase (GST), and uridine glucuronyl transferase (UGT) as evidenced by the qPCR analysis. Immunoblot analysis revealed that onset of oxidative stress and angiogenesis in the colon of DMH alone administered rats were due to downregulation of pPERK along with its downstream targets such as peIF2α and CHOP. Supplementation of morin reversed the DMH-induced alterations and suppresses oxidative stress and angiogenesis via PERK phosphorylation.

Keywords:

• Morin
• angiogenesis
• oxidative stress
• PERK
• UPR
• CHOP
• Nrf2

Acknowledgement

The authors thank Dr. S. Swaminathan (Director, CeNTAB) and Dr. S. Anuradha (Co Investigator, DBT BioCARe) of SASTRA Deemed University for their great support to perform the study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Department of Biotechnology [grant number BT/Bio-CARe/07/10037/2013-14] and the Ministry of Science and Technology, New Delhi, India.