Integrated proteomics and metabolomics reveals the comprehensive characterization of antitumor mechanism underlying Shikonin on colon cancer patient-derived xenograft model

Abstract

colorectal cancer (cRc) is a common malignancy occurring in the digestive system. Despite progress in surgery and therapy options, cRc is still a considerable cause of cancer mortality worldwide. in this study, a colon cancer patient-derived xenograft model was established to evaluate the antitumor activity of Shikonin. The protective effect underlying Shikonin was determined through assessing serum levels of liver enzymes (ALt, ASt) and kidney functions (Bun, Scr) in pDX mice. proteomics and metabolomics profiles were integrated to provide a systematic perspective in dynamic changes of proteins and global endogenous metabolites as well as their perturbed pathways. A total of 456 differently expressed proteins (DEPs), 32 differently expressed metabolites (DEMs) in tumor tissue, and 20 DEMs in mice serum were identified. The perturbation of arginine biosynthesis, purine metabolism, and biosynthesis of amino acids may mainly account for therapeutic mechanism of Shikonin. Furthermore, the expression of mRNAs participating in arginine biosynthesis (CPS1, OTC, Arg1) and do novo purine synthesis (GART, PAICS, ATIC) were validated through RT-qPCR. Our study provides new insights into the drug therapeutic strategies and a better understanding of antitumor mechanisms that might be valuable for further studies on Shikonin in the clinical treatment of colorectal cancer. Colorectal cancer (CRC), a digestive system tumor, is currently the third most common malignant cancer worldwide 1. Despite the improvements in diagnosis and therapeutic methods, the high risk of liver metastasis and poor prognosis of patients with advanced colorectal cancer remain to be addressed 2. Currently, surgery combined with chemotherapy and radiotherapy is still served as the predominant treatment for colorectal cancer. However, their side effects are considerable. Hence, the development of natural products has become a priority for the therapy of colorectal cancer. Shikonin (SHK), a naphthoquinone pigment isolated from the root of Lithospermum erythrorhizon (Sieb. et Zucc, Boraginaceae) (Fig. 1), has been reported to be highly effective against a variety of cancer types during the past decades 3. Shikonin was demonstrated to suppress proliferation and induce cell cycle arrest in human colon cancer through inhibiting hypoxia-inducible factor-1 alpha signaling both in vitro and vivo 4. Shikonin induced

Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL‑6/STAT3 signaling pathway

“…However, similar to other natural products in Chinese herbal medicine, the potential toxicity and unknown side-effects of SKN merit accelerated investigations. Indeed, SKN can affect multiple biological processes, including protein translation, folding, modification and translocation, as well as exosome secretion and energy production (71). To date, the antitumor properties of SKN have been demonstrated in several in vivo studies on colon cancer (71)(72)(73).…”

“…Indeed, SKN can affect multiple biological processes, including protein translation, folding, modification and translocation, as well as exosome secretion and energy production (71). To date, the antitumor properties of SKN have been demonstrated in several in vivo studies on colon cancer (71)(72)(73). Moreover, it has been proven that SKN functions as a complement to enhance the antitumor effect of cisplatin in colon cancer in vivo (74).…”

Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia

“…According to a report from The Human Protein Atlas, ATIC has a strong immunoreactivity in CRC tissue ( ). Moreover, ATIC is one of the differentially expressed proteins associated with drug response in CRC ( 34 ). PDE5A plays an essential role in signal transduction by regulating the intracellular concentration of cyclic nucleotides ( 35 ).…”

Traditional Chinese Medicine and Colorectal Cancer: Implications for Drug Discovery

“…Additionally, the effects of shikonin on the survival and tumor growth of the nude mice model, as well as the migration and invasion of human CRC cells, appear to be able to imply the fact that shikonin inhibited the metastasis of CRC through SIRT2- (silent information regulators 2-) mediated antitumor effect ( Zhang et al, 2017b ). Furthermore, the anti-CRC activity of shikonin was also validated by the approaches of metabolomics, transcriptomics, and proteomics ( Chen et al, 2020c ; Chen et al, 2020d ). In short, shikonin is a potentially effective agent for the treatment of CRC, which has attention-grabbing clinical application and research value.…”