AUTHOR=Liu Wenna , Zhao Yujia , Liu Qingqing , Wu Dan , Li Wenxuan , Fu Zhenkai , Yang Le , Liang Ying 

TITLE=Systematic bioinformatics analysis reveals the role of shikonin in blocking colon cancer progression by identifying senescence-induced genes

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1360587

DOI=10.3389/fphar.2024.1360587

ISSN=1663-9812

ABSTRACT=<p>Shikonin, a naturally occurring naphthoquinone compound extracted from comfrey plants, has antitumor, anti-inflammatory, and antimicrobial properties. Cell senescence plays a key role in preventing tumor progression. It is unclear whether shikonin has an effect on cell senescence in colon cancer. In the current study, we first determine the IC<sub>50</sub> values of shikonin on colon cancer cell lines HT29 and HCT116. Then, we verified the inhibitory effects of shikonin on the proliferation and migration abilities of colon cancer cell lines HT29 and HCT116 using cell counting kit-8, colony formation, and wound healing assays. Next, we identified a series of potential targets using high-throughput mRNA sequencing and identified 210 upregulated and 296 downregulated genes. KEGG profiling revealed eight downregulated genes associated with cell senescence: <italic>CCNB3</italic>, <italic>IL-1α</italic>, <italic>CXCL8</italic>, <italic>CDKN2A</italic>, <italic>MYC</italic>, <italic>IGFBP3</italic>, <italic>SQSTM1</italic>, and <italic>GADD45G</italic>. Among them, <italic>CXCL8</italic> and <italic>CDKN2A</italic> were associated with poor prognosis in patients with colon cancer, suggesting that their downregulation by shikonin could improve patient survival. Furthermore, SA-β-galactosidase staining revealed that the percentage of cellular senescence in colon cancer cells was significantly increased after shikonin treatment. Molecular docking revealed that shikonin suppressed colon cancer progression by blocking <italic>CXCL8</italic> activity. Based on these findings, we deem that shikonin might induce senescence and exert antitumor activity in colon cancer cells by downregulating <italic>CDKN2A</italic> and <italic>CXCL8</italic>. This provides a new molecular mechanism and potential therapeutic target for shikonin to inhibit colon cancer progression.</p>