Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways

Abstract

2019) Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways, Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 626-635, ABSTRACT Shikonin, a botanical drug extracted from Lithospermum erythrorhizon, exhibits anti-cancer effects in various cancer cell lines. However, the mechanisms underlying these effects have not been completely elucidated yet. Here, we showed that Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation. Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1. Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2a, CHOP, and cleaved caspase-3. It also induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1. Upon suppression of autophagy by 3-methyladenine, Shikonin-induced apoptosis was enhanced in A375 cells. Moreover, after pretreatment with N-acetyl-cysteine, Shikonin increased the production of reactive oxygen species that are involved in regulating ER stress-mediated apoptosis and p38-activated autophagy, as evidenced by the reversion of cell viability and apoptosis and a decrease in p-eIF2a, CHOP, p-p38, LC3B-II, and Beclin 1 levels. Thus, we demonstrated that Shikonin induced apoptosis and autophagy in A375 cells via the activation of ROS-mediated ER stress and p38 pathways, indicating that Shikonin can serve as a potential agent for human melanoma therapy. ARTICLE HISTORY

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…It can also induce necroptosis via autophagy inhibition in human NSCLC A549 cells [593], and through ROS overproduction in human nasopharyngeal carcinoma 5-8F, and glioma SHG-44, U87 and U251 cells [606,607]. Moreover, shikonin induces autophagy in human melanoma A375, pancreatic cancer BxPC-3, and hepatocellular carcinoma Bel-7402 and Huh7 cells [608][609][610]. However, autophagy provides a protective role in shikonin-induced apoptosis in human melanoma A375 cells [608].…”

“…Moreover, shikonin induces autophagy in human melanoma A375, pancreatic cancer BxPC-3, and hepatocellular carcinoma Bel-7402 and Huh7 cells [608][609][610]. However, autophagy provides a protective role in shikonin-induced apoptosis in human melanoma A375 cells [608]. In addition, shikonin can suppress metastasis by the inhibition of tyrosine kinase c-Met and integrin (ITG) β1 in human NSCLC A549 cells [602,611].…”

<p>Regulations of miR-183-5p and Snail-Mediated Shikonin-Reduced Epithelial-Mesenchymal Transition in Cervical Cancer Cells</p>

“…Shikonin, a natural naphthoquinone component extracted from the root of Lithospermum erythrorhizon and Arnebia euchroma (Royle) Johnst native to China, hold promising potentials for antitumor effects via multiple-target mechanisms. [4][5][6][7][8] It was reported that the anti-migration and anti-invasion activities of shikonin was through inhibition of c-Met followed by suppression of epithelial-mesenchymal transition (EMT) in lung cancer cells. 9 Shikonin showed to exert anticancer effects on gallbladder cancer (GBC) cells by inducing apoptosis and regulating the cell cycle arrest via the c-Jun N-terminal kinase (JNK) signaling pathway.…”

Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma

“…ROS is an important signaling molecule in various vital cellular processes, including cell apoptosis, autophagy, proliferation, and differentiation [41]. Many studies have found that excessive accumulation of intracellular ROS caused irreversible cellular damage leading to autophagy and/or apoptosis [42,43]. Chao…”