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. 2021 Jul;24(1):482.
doi: 10.3892/mmr.2021.12121. Epub 2021 Apr 28.

The natural product lapiferin inhibits cell proliferation and promotes cell apoptosis in gingival squamous cell carcinoma via P21 regulation

Affiliations

The natural product lapiferin inhibits cell proliferation and promotes cell apoptosis in gingival squamous cell carcinoma via P21 regulation

Lin Liu et al. Mol Med Rep. 2021 Jul.

Abstract

Gingival squamous cell carcinoma (GSCC) is responsible fora large proportion of oral cavity malignancies. GSCC is characterized by rapid cell growth, and progressive invasion and migration. P21 is a widely recognized tumor suppressor, which is induced by P53 activation; however, drugs that aim to promote P21‑mediated tumor suppression remain to be identified. A natural compound library was used to perform broad‑spectrum screening of drugs that could promote P21 expression. Subsequently, the effects of the screened drug on GSCC cell proliferation and apoptosis were evaluated. The results of the present study suggested that lapiferin was the most effective natural compound that promoted the expression of P21 at both mRNA and protein levels. Lapiferin inhibited proliferation and enhanced apoptosis of YD‑38 GSCC cells in a dose‑dependent manner. Furthermore, following treatment with lapiferin, the critical cell cycle regulators cell division cycle 25C and cyclin B1 and tumor cell proliferation markers proliferating cell nuclear antigen and Ki67 were markedly decreased. In addition, pro‑apoptotic proteins were promoted following treatment of YD‑38 cells with lapiferin. Following the depletion ofP21 expression, lapiferin‑mediated inhibition of cell proliferation and enhancement of cell apoptosis were significantly reduced. These results indicated that lapiferin may exert potent antitumor effects on GSCC via regulation of P21; therefore, lapiferin may be considered a potential, natural therapeutic agent for the treatment of GSCC.

Keywords: P21; apoptosis; gingival carcinoma; lapiferin; proliferation.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Lapiferin promotes P21 luciferase activity in the YD-38 human gingival squamous cell carcinoma cell line. Luciferase activities were detected to assess the effects of 480 natural products on the transcriptional activities of P21.
Figure 2.
Figure 2.
Lapiferin decreases cell proliferation in a dose- and time-dependent manner in GSCC. (A) YD-38 human GSCC cells were treated with increasing doses of lapiferin for 24 h and cell proliferative rates were assessed at a wavelength of 490 nm. (B) YD-38 human GSCC cells were treated with lapiferin (10 µg/ml) for increasing durations and cell proliferative rates were assessed at a wavelength of 490 nm. *P<0.05 vs. control. GSCC, gingival squamous cell carcinoma; OD, optical density.
Figure 3.
Figure 3.
Lapiferin increases cell apoptosis in a dose- and time-dependent manner in GSCC. (A) YD-38 human GSCC cells were treated with increasing doses of lapiferin for 24 h and relative cell apoptotic rates normalized to the control group were assessed. (B) YD-38 human GSCC cells were treated with lapiferin (10 µg/ml) for increasing durations and relative cell apoptotic rates normalized to the control group were assessed. (C) Flow cytometry plots for cell apoptosis. *P<0.05 vs. control. GSCC, gingival squamous cell carcinoma; OD, optical density.
Figure 4.
Figure 4.
Lapiferin suppresses the protein expression levels of cell proliferation regulators in YD-38 cells. YD-38 cells were treated with lapiferin for 24 h at a dose of 10 µg/ml, and the protein expression levels of P21, PCNA, Ki67, Cdc 25C, cyclinB1 and GAPDH were examined by western blot analysis. GAPDH was used as an internal control. Cdc 25C, cell division cycle 25C; PCNA, proliferating cell nuclear antigen.
Figure 5.
Figure 5.
Lapiferin increases pro-apoptotic protein expression in YD-38 cells. YD-38 cells were treated with lapiferin for 24 h at a dose of 10 µg/ml, and the protein expression levels of cl-caspase-3, cl-caspase-9, Bax, cyto. C, cl-PARP and GAPDH were examined by western blot analysis. GAPDH was used as an internal control. cl, cleaved; Cyto. C, cytochrome c; PARP, poly (ADP-ribose) polymerase.
Figure 6.
Figure 6.
Lapiferin decreases cell proliferation and increases cell apoptosis through regulating P21 in human gingival squamous cell carcinoma. (A) P21 mRNA expression levels were detected using reverse transcription-quantitative PCR when YD-38 cells were transfected with or without siP21 in the presence or absence of lapiferin. (B) Cell proliferation was detected when YD-38 cells were transfected with or without siP21 in the presence or absence of lapiferin. (C) Relative cell apoptosis normalized to the control group was detected when YD-38 cells were transfected with or without siP21 in the presence or absence of lapiferin. (D) Flow cytometry plots for cell apoptosis. *P<0.05, as indicated. NC, negative control; OD, optical density; si, small interfering RNA.

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