Abstract
Background and PurposeOverexpression 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 ApproachTargets of acetylshikonin, were identified using kinase profiling analysis, kinetic/binding assay, and computational docking analysis and knock‐down 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 ResultsAcetylshikonin 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, acetylshikonin diminished the phosphorylation and activation of TOPK signalling. Furthermore, acetylshikonin decreased the volume of PDX tumours and reduced the expression of TOPK signalling pathway in xenograft tumours.Conclusion and ImplicationsAcetylshikonin suppressed growth of colorectal cancer cells by attenuating TOPK signalling. Targeted inhibition of TOPK by acetylshikonin might be a promising new approach to the treatment of colorectal cancer.
Highlights
Colorectal cancer is one of the most common causes of cancer-related death
One of the emerging oncogenic signalling molecules is an intracellular protein kinase, the T-lymphokine-activated killer cell-originated protein kinase (TOPK; known as PDZ binding kinase, PBK), which has been implicated in the development and progression of gastric (Ohashi et al, 2017) and ovarian cancers (Ikeda et al, 2016), oesophageal squamous cell carcinomas (Ohashi et al, 2016), and colorectal cancer (Zlobec et al, 2010)
Because the initial assessment of the expression of phosphorylated TOPK (pTOPK), TOPK, and the members of TOPK signalling pathway, such as pERK, pRSK, and phosphorylated c-Jun (pc-Jun), was elevated in HCT-15, HCT-116, SW 620, and DLD-1 colon cancer cells, compared to HT-29 and SW 480 colon cancer cells (Figure S2B), we studied the effects of acetylshikonin on HCT-15, HCT-116, SW 620, and DLD-1 colon cancer cell lines
Summary
Colorectal cancer is one of the most common causes of cancer-related death. It comprises a substantial proportion of the global burden of cancer morbidity and mortality, being the fourth most common cause of cancer mortality, accounting for 600,000 deaths annually (Rossi, Anwar, Usman, Keshavarzian, & Bishehsari, 2018). We have attempted to evaluate the potential of developing acetylshikonin, a major biologically active compound present in Lithospermum erythrorhizon root (Cho, Paik, & Hahn, 1999; Rajasekar et al, 2012), as a TOPK inhibitor and assess its anti-cancer effects in cultureds of colorectal cancer cells and in patient-derived xenograft (PDX) tumour models in mice. Acetylshikonin reportedly inhibits human pancreatic cancer cell proliferation through inhibition of NF-κB activity, attenuates HepG2 hepatoma cell growth by suppressing CYP2J2, and reduces obesity and hepatic steatosis in db/ db mice (Cho & Choi, 2015; Gwon, Ahn, Chung, Moon, & Ha, 2012; Park et al, 2017) These findings led us to examine whether acetylshikionin could inhibit colorectal tumour growth and to elucidate its underlying mechanisms. Our study suggests that acetylshikonin, as an inhibitor of TOPK, may be a potential candidate for clinical development as an anticancer therapy for colorectal cancer
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