Acetylshikonin suppressed growth of colorectal tumour tissue and cells by inhibiting the intracellular kinase, T‐lymphokine‐activated killer cell‐originated protein kinase.

Abstract

Background and Purpose: Overexpression or aberrant activation of the T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes gene expression and growth of solid tumours, implying that TOPK would be a rational target in developing novel anticancer drugs. Acetylshikonin, a diterpenoid compound isolated from Lithospermum erythrorhizon root, exerts a range of biological activities. Here we have investigated whether acetylshikonin, by acting as an inhibitor of TOPK, can attenuate the proliferation of colorectal cancer cells and the growth of patient-derived tumours, in vitro and in vivo. Experimental Approach: Targets of acetylshikonin, were identified using kinase profiling analysis, kinetic/binding assay, and computational docking analysis and knockdown techniques. Effects of acetylshikonin on colorectal cancer growth and the underlying mechanisms were evaluated in cell proliferation assays, propidium iodide and annexin-V staining analyses and western blots. Patient-derived tumour xenografts in mice (PDX) and immunohistochemistry were used to assess anti-tumour effects of acetylshikonin. Key Results: Acetylshikonin directly inhibited TOPK activity, interacting with the ATP-binding pocket of TOPK. Acetylshikonin suppressed cell proliferation by inducing cell cycle arrest at the G1 phase, stimulated apoptosis, and increased the expression of apoptotic biomarkers in colorectal cancer cell lines. Mechanistically, Abbreviations: PDX, patient-derived tumour xenograft; RSK, ribosomal s6 kinase; TOPK, T (T-LAK)-cell-originated protein kinase.Ran Zhao, Bu Young Choi, Lixiao Wei, and Mangaladoss Fredimoses equally contributed in this study.

Acetylshikonin Suppresses Diffuse Large B-Cell Lymphoma Cell Growth By Targeting The TOPK Signaling Pathway

“…So we estimated that acetylshikonin was more suitable targeted compound for DLBCL. The observed anti-cancer effects of acetylshikonin was reported in human pancreatic panc-1 cancer cells and colon cancer cells [13,27]. In our studies, we demonstrated that acetylshikonin inhibited cell proliferation (Fig.…”

“…An ideal anti-cancer compound should lack cytotoxicity against normal cells. In this study, we choose two native compound (acetylshikonin and 3-DSC) which were extracted from plants and showed anti-cancer effects by target TOPK [13,14]. Our data indicated that acetylshikonin showed no cytotoxicity up to 20 µM at 72 h (Fig.…”

“…Moreover, acetylshikonin, another TOPK inhibitor, reduces colorectal cancer cells proliferation and decreases the volume of patient-derived xenograft (PDX) tumors in mice [13]. These studies suggest that TOPK may be a promising target for anticancer therapy.…”

“…Previously studies have shown that acetylshikonin and 3-DSC could suppress colon cancer cell growth [13,14]. To study the effects of acetylshikonin and 3-DSC on DLBCL cell growth, we rst assessed the effect of acetylshikonin and 3-DSC on the proliferation of normal B-cell line.…”

“…TOPK promotes cancer cell proliferation by its phosphorylation of ERKs [11,12]. The knockdown of TOPK will activate cysteine proteases (caspase − 3 and caspase − 7) and nally kill the cancer cells [13,14]. In primary central nervous system lymphoma (PCNSL), TOPK can be a potent novel biomarker, and its overexpression is associated with poor prognosis of PCNSL [15].…”