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. 2021 Nov 2:11:768879.
doi: 10.3389/fonc.2021.768879. eCollection 2021.

Dihydroartemisinin Suppresses the Tumorigenesis and Cycle Progression of Colorectal Cancer by Targeting CDK1/CCNB1/PLK1 Signaling

You-Cai Yi  1 , Rui Liang  1 , Xiao-Yu Chen  1 , Hui-Ning Fan  1 , Ming Chen  1 , Jing Zhang  1 , Jin-Shui Zhu  1
Affiliations

Dihydroartemisinin Suppresses the Tumorigenesis and Cycle Progression of Colorectal Cancer by Targeting CDK1/CCNB1/PLK1 Signaling

You-Cai Yi et al. Front Oncol. .

Retraction in

Abstract

Dihydroartemisinin (DHA), a well-known antimalarial drug, has been widely investigated for its antitumor effects in multiple malignancies. However, its effects and regulatory mechanisms in colorectal cancer (CRC) are still unproved. In this study, in vitro experiments including CCK8, EdU, Transwell, and flow cytometry analyses and an in vivo tumorigenesis model were conducted to assess the effects of DHA on the bio-behaviors of CRC cells. Additionally, RNA-seq combined with gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses was used to obtain the targets of DHA, and these were verified by molecular docking, qRT-PCR, and Western blotting. As a result, we found that DHA significantly suppressed the proliferation, DNA synthesis, and invasive capabilities and induced cell apoptosis and cell cycle arrest in HCT116, DLD1, and RKO cells in vitro and in vivo. Further analyses indicated that the targets of DHA were predominantly enriched in cell cycle-associated pathways, including CDK1, CCNB1, and PLK1; and DHA could bind with the CDK1/CCNB1 complex and inhibit the activation of CDK1/CCNB1/PLK1 signaling. Moreover, cucurbitacin E, a specific inhibitor of the CDK1/CCNB1 axis, enhanced the inhibitory effects of DHA on DNA synthesis and colony formation in HCT116 and DLD1 cells. In short, DHA could suppress the tumorigenesis and cycle progression of CRC cells by targeting CDK1/CCNB1/PLK1 signaling.

Keywords: CCNB1; CDK1; cell cycle; colorectal cancer; dihydroartemisinin; growth.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
DHA inhibited the proliferation, colony formation, and DNA synthesis in CRC cells. (A) The IC50 of DHA was detected by the CCK8 assay in HCT116 cells. (B–D) The effects of DHA on cell viabilities were examined by the CCK8 assay. (E, F) The effects of DHA on cell colony formation were illustrated by the cell colony formation assay. (G, H) The effects of DHA on DNA synthesis were examined by the EdU assay. Data are shown as means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. DHA, dihydroartemisinin; CRC, colorectal cancer.
Figure 2
Figure 2
DHA inhibited the invasive abilities of CRC cells. (A–D) The effects of DHA on cell mobilities were detected by the wound healing assay at different time points. (E, F) The effects of DHA on cell migration and invasion were assessed by the Transwell assay. Data are shown as means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. DHA, dihydroartemisinin; CRC, colorectal cancer.
Figure 3
Figure 3
DHA caused cell cycle arrest in the G2/M phase and induced cell apoptosis. (A) The effects of DHA on cell cycle distribution were examined by flow cytometry. (B) The effects of DHA on cell apoptosis were examined by flow cytometry. Data are shown as means ± SD. **p < 0.01, ***p < 0.001. DHA, dihydroartemisinin.
Figure 4
Figure 4
DHA regulated CDK1/CCNB1/PLK1 signaling in CRC cells. (A) A heatmap showing the top 100 DEGs in DHA-treated CRC cells. (B, C) KEGG and GO analyses of the targeted of DHA in CRC cells. (D, E) qRT-PCR and Western blotting analysis of the effects of DHA on the expression of CDK1, CCNB1, and PLK1 in CRC cells. Data are shown as means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. DHA, dihydroartemisinin; CRC, colorectal cancer; DEGs, differentially expressed genes; KEGG, Kyoto Encyclopedia of Genes and Genomes; GO, Gene Ontology.
Figure 5
Figure 5
DHA synergizes with cucurbitacin E to inhibit the growth of CRC cells. (A) The effects of DHA and CE on cell cycle distribution were examined by flow cytometry. (B) The effects of DHA and CE on cell colony formation were illustrated by the cell colony formation assay. (C) The effects of DHA and CE on DNA synthesis were examined by EdU assay. (D, E) qRT-PCR and Western blotting analysis of the effects of DHA and CE on the expression of CDK1, CCNB1, and PLK1 in CRC cells. Data are shown as means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. DHA, dihydroartemisinin; CRC, colorectal cancer; CE, cucurbitacin E.
Figure 6
Figure 6
DHA suppressed the in vivo tumorigenesis of CRC. (A) Representative images of xenograft tumors are shown. (B, C) The growth curves of tumor volumes were plotted, and the tumor weight of each mouse was measured. (D, E) Representative images of IHC images of Ki-67, CDK1, CCNB1, and PLK1 and H&E staining in control and DHA treatment groups. Data are shown as means ± SD. *p < 0.05, ***p < 0.001. DHA, dihydroartemisinin; CRC, colorectal cancer; IHC, immunohistochemistry.
Figure 7
Figure 7
Molecular mechanisms of DHA in CRC. (A) Molecular docking of DHA into the protein crystal of the CDK1/CCNB1 complex. (B) DHA suppressed the tumorigenesis and cycle progression of CRC by targeting CDK1/CCNB1/PLK1 signaling. DHA, dihydroartemisinin; CRC, colorectal cancer.
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