Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.088
Natural Compound Shikonin Induces Apoptosis and Attenuates Epithelial to Mesenchymal Transition in Radiation-Resistant Human Colon Cancer Cells
Kristina Shilnikova, Mei Jing Piao, Kyoung Ah Kang, Pincha Devage Sameera Madushan Fernando, Herath Mudiyanselage Udari Lakmini Herath, Suk Ju Cho* and Jin Won Hyun*
College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
*E-mail: sukjucho@gmail.com (Cho SJ), jinwonh@jejunu.ac.kr (Hyun JW)
Tel: +82-64-717-2062 (Cho SJ), +82-64-754-3838 (Hyun JW)
Fax: +82-504-226-8173 (Cho SJ), +82-64-702-2687 (Hyun JW)
Received: May 7, 2021; Revised: June 7, 2021; Accepted: June 8, 2021; Published online: July 29, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Radiation resistance represents an imperative obstacle in the treatment of patients with colorectal cancer, which remains difficult to overcome. Here, we explored the anti-proliferative and migration-inhibiting properties of the natural product shikonin on a radiation-resistant human colon carcinoma cell line (SNU-C5RR). Shikonin reduced the viability of these cells in a dose-dependent manner; 38 μM of shikonin was determined as the half-maximal inhibitory concentration. Shikonin induced apoptotic cell death, as demonstrated by increased apoptotic body formation and the number of TUNEL-positive cells. Moreover, shikonin enhanced mitochondrial membrane depolarization and Bax expression and also decreased Bcl-2 expression with translocation of cytochrome c from mitochondria into the cytosol. In addition, shikonin activated mitogen-activated protein kinases, and their specific inhibitors reduced the cytotoxic effects of shikonin. Additionally, shikonin decreased the migration of SNU-C5RR cells via the upregulation of E-cadherin and downregulation of N-cadherin. Taken together, these results suggest that shikonin induces mitochondria-mediated apoptosis and attenuates epithelial-mesenchymal transition in SNU-C5RR cells.
Keywords: Shikonin, Radiation resistance, Human colon cancer, Epithelial to mesenchymal transition, Mitochondria-mediated apoptosis, Mitogen-activated protein kinases


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