Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May 9;22(9):5022.
doi: 10.3390/ijms22095022.

Trichodermin Induces G0/G1 Cell Cycle Arrest by Inhibiting c-Myc in Ovarian Cancer Cells and Tumor Xenograft-Bearing Mice

Affiliations

Trichodermin Induces G0/G1 Cell Cycle Arrest by Inhibiting c-Myc in Ovarian Cancer Cells and Tumor Xenograft-Bearing Mice

Ying Gao et al. Int J Mol Sci. .

Abstract

Ovarian cancer is a fatal gynecological cancer because of a lack of early diagnosis, which often relapses as chemoresistant. Trichodermin, a trichothecene first isolated from Trichoderma viride, is an inhibitor of eukaryotic protein synthesis. However, whether trichodermin is able to suppress ovarian cancer or not was unclear. In this study, trichodermin (0.5 µM or greater) significantly decreased the proliferation of two ovarian cancer cell lines A2780/CP70 and OVCAR-3. Normal ovarian IOSE 346 cells were much less susceptible to trichodermin than the cancer cell lines. Trichodermin predominantly inhibited ovarian cancer cells by inducing G0/G1 cell cycle arrest rather than apoptosis. Trichodermin decreased the expression of cyclin D1, CDK4, CDK2, retinoblastoma protein, Cdc25A, and c-Myc but showed little effect on the expression of p21Waf1/Cip1, p27Kip1, or p16Ink4a. c-Myc was a key target of trichodermin. Trichodermin regulated the expression of Cdc25A and its downstream proteins via c-Myc. Overexpression of c-Myc attenuated trichodermin's anti-ovarian cancer activity. In addition, trichodermin decelerated tumor growth in BALB/c nude mice, proving its effectiveness in vivo. These findings suggested that trichodermin has the potential to contribute to the treatment of ovarian cancer.

Keywords: A2780/CP70 cells; Cdc25A; OVCAR-3 cells; c-Myc; cell cycle arrest; trichodermin.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Trichodermin preferentially decreased the proliferation of human ovarian cancer cells. (A) Chemical structure of trichodermin. (B) The impacts of trichodermin on the proliferation of two human ovarian cancer cell lines (A2780/CP70 and OVCAR-3 cells) and one normal human ovarian surface epithelial cell line (IOSE-364 cells) after 24 h treatment. (C) The impacts of trichodermin on the viability of A2780/CP70 and OVCAR-3 cells after 24 h treatment. * p < 0.05 compared with the control group.
Figure 2
Figure 2
Trichodermin induced G0/G1 cell cycle arrest in A2780/CP70 and OVCAR-3 cells after 24 h treatment. The cell distribution was measured using flow cytometry. (A) Flow cytometry plots. (B) The cell cycle distribution of A2780/CP70 cells and OVCAR-3 cells after trichodermin treatment. * p < 0.05 compared with the control group.
Figure 3
Figure 3
Trichodermin suppressed the expression of cyclin D1, cyclin-dependent kinases (CDKs), phosphor-retinoblastoma protein (p-Rb), Rb, Cdc25A, and c-Myc after 24 h treatment. However, it minimally affected the expression of CDK inhibitors (CDKIs), including p27Kip1 (p27), p21Waf1/Cip1 (p21), and p16Ink4a (p16). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as the loading control. * p < 0.05 compared with the control group.
Figure 4
Figure 4
Overexpression of c-Myc attenuated trichodemin-induced G0/G1 cell cycle arrest in A2780/CP70 and OVCAR-3 cells. (A) Flow cytometry plots. (B) The cell cycle distribution of A2780/CP70 cells and OVCAR-3 cells after plasmid transfection and trichodermin treatment. * p < 0.05 compared with the specific group.
Figure 5
Figure 5
Overexpression of c-Myc attenuated trichodermin-induced suppression of c-Myc, Cdc25A, phosphor-retinoblastoma protein (p-Rb), and Rb in A2780/CP70 and OVCAR-3 cells. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as the loading control. * p < 0.05 compared with the specific group.
Figure 6
Figure 6
Trichodermin inhibited the growth of OVCAR-3 xenografts in BALB/C nude mice. OVCAR-3 human ovarian cancer cell suspension (containing 5 × 106 cells) was mixed with Matrigel (1:1, v/v) and implanted subcutaneously between the scapula of nude mice. After palpable tumors were formed (tumor size > 30–60 mm3), mice were injected three times weekly with 0.2 mL vehicle (sterile PBS) or trichodermin (5 mg/kg body weight, dissolved in pre-warmed sterile PBS) for four weeks. (A) Tumor size at Day 28 of trichodermin (5 mg/kg body weight) or vehicle treatment. (B) Body weight during the four-week treatment of trichodermin (5 mg/kg body weight) or vehicle. (C) Body weight at Day 28 of trichodermin (5 mg/kg body weight) or vehicle treatment. (D) Food intake and (E) water intake during the four-week treatment of trichodermin (5 mg/kg body weight) or vehicle. * p < 0.05 compared with the control group.

Similar articles

Cited by

References

    1. Siegel R.L., Miller K.D., Fuchs H.D., Jemal A. Cancer statistics, 2021. CA Cancer J. Clin. 2021;71:7–33. doi: 10.3322/caac.21654. - DOI - PubMed
    1. Morgan R.J., Jr., Alvarez R.D., Armstrong D.K., Burger R.A., Chen L.M., Copeland L., Crispens M.A., Gershenson D.M., Gray H.J., Hakam A., et al. Ovarian cancer, version 2. 2013. J. Natl. Compr. Cancer Netw. 2013;11:1199–1209. doi: 10.6004/jnccn.2013.0142. - DOI - PubMed
    1. Targeted Cancer Therapies. [(accessed on 27 July 2020)]; Available online: https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/t....
    1. McDonald M.E., Salinas E.A., Devor E.J., Newtson A.M., Thiel K.W., Goodheart M.J., Bender D.P., Smith B.J., Leslie K.K., Gonzalez-Bosquet J. Molecular characterization of non-responders to chemotherapy in serous ovarian cancer. Int. J. Mol. Sci. 2019;20:1175. doi: 10.3390/ijms20051175. - DOI - PMC - PubMed
    1. Chase D.M., Mathur N., Tewari K.S. Drug discovery in ovarian cancer. Recent Pat. Anticancer Drug Discov. 2010;5:251–260. doi: 10.2174/157489210791760472. - DOI - PubMed