Targeting the BMI1-Noxa Axis by Dioscin Induces Apoptosis in Oral Squamous Cell Carcinoma Cells

Overview

Journal J Cancer

Specialty Oncology

Date 2025 Jan 2

PMID 39744574

Authors

Jinglin Fang

Ruirui Wang

Xiaoying Li

Xiaocong Wang

Lingling Gong

An Lou

Jie Lu

Xiaoyue Zhang

Qin Zhao

Xinfang Yu

Qiling Zhou

Ming Li

Affiliations

Soon will be listed here.

Abstract

Dioscin is a natural plant-derived steroidal saponin that exerts antitumor effects in multiple cancers. It is widely involved in multiple apoptotic pathways and exerts its anti-tumor effects. In this study, we discovered that Dioscin treatment increased the expression of Noxa, thereby inducing the apoptosis of OSCC cells. Previous reports indicate that dysfunction of the BMI1-Noxa axis is frequently observed in multiple cancers. Our study revealed that Dioscin upregulates Noxa by impairing the protein expression of BMI1 in OSCC cells. Dioscin promotes the ubiquitination of BMI1 and facilitates its degradation, leading to upregulation of Noxa expression at the mRNA level and activation of apoptosis. Additionally, Dioscin exhibited potent tumor suppression in xenograft tumor models. In conclusion, our research provides new insights and strategies for inhibiting OSCC cells by investigating the ant-tumor mechanism of the natural compound Dioscin.

References

Sahasrabuddhe A, Dimri M, Bommi P, Dimri G . βTrCP regulates BMI1 protein turnover via ubiquitination and degradation. Cell Cycle. 2011; 10(8):1322-30. PMC: 3117138. DOI: 10.4161/cc.10.8.15372. View

Zhang F, Sui L, Xin T . Correlations of BMI-1 expression and telomerase activity in ovarian cancer tissues. Exp Oncol. 2008; 30(1):70-4. View

Dimri G, Martinez J, Jacobs J, Keblusek P, Itahana K, van Lohuizen M . The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res. 2002; 62(16):4736-45. View

Ou-Yang S, Jiang T, Zhu L, Yi T . Dioscorea nipponica Makino: a systematic review on its ethnobotany, phytochemical and pharmacological profiles. Chem Cent J. 2018; 12(1):57. PMC: 5945570. DOI: 10.1186/s13065-018-0423-4. View

Bugshan A, Farooq I . Oral squamous cell carcinoma: metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis. F1000Res. 2020; 9:229. PMC: 7194458. DOI: 10.12688/f1000research.22941.1. View

Xu L, Yin L, Jin Y, Qi Y, Han X, Xu Y . Effect and possible mechanisms of dioscin on ameliorating metabolic glycolipid metabolic disorder in type-2-diabetes. Phytomedicine. 2019; 67:153139. DOI: 10.1016/j.phymed.2019.153139. View

Vonlanthen S, Heighway J, Altermatt H, Gugger M, Kappeler A, Borner M . The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer. 2001; 84(10):1372-6. PMC: 2363629. DOI: 10.1054/bjoc.2001.1791. View

Bottner M, Laaff M, Schechinger B, Rappold G, Unsicker K, Suter-Crazzolara C . Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1). Gene. 1999; 237(1):105-11. DOI: 10.1016/s0378-1119(99)00309-1. View

Kim J, Ahn H, Ryu J, Suk K, Park J . BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. J Exp Med. 2003; 199(1):113-24. PMC: 1887730. DOI: 10.1084/jem.20030613. View

10.

Yamashita M, Kuwahara M, Suzuki A, Hirahara K, Shinnaksu R, Hosokawa H . Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene. J Exp Med. 2008; 205(5):1109-20. PMC: 2373843. DOI: 10.1084/jem.20072000. View

11.

Ploner C, Kofler R, Villunger A . Noxa: at the tip of the balance between life and death. Oncogene. 2009; 27 Suppl 1:S84-92. PMC: 3272398. DOI: 10.1038/onc.2009.46. View

12.

Goebl M . The bmi-1 and mel-18 gene products define a new family of DNA-binding proteins involved in cell proliferation and tumorigenesis. Cell. 1991; 66(4):623. DOI: 10.1016/0092-8674(91)90106-9. View

13.

Yao H, Tao X, Xu L, Qi Y, Yin L, Han X . Dioscin alleviates non-alcoholic fatty liver disease through adjusting lipid metabolism via SIRT1/AMPK signaling pathway. Pharmacol Res. 2018; 131:51-60. DOI: 10.1016/j.phrs.2018.03.017. View

14.

Chen L, Willis S, Wei A, Smith B, Fletcher J, Hinds M . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005; 17(3):393-403. DOI: 10.1016/j.molcel.2004.12.030. View

15.

Ma T, Ge X, Zhu J, Song C, Wang P, Cai J . Dioscin Impedes Proliferation, Metastasis and Enhances Autophagy of Gastric Cancer Cells via Regulating the USP8/TGM2 Pathway. Mol Biotechnol. 2023; 66(12):3700-3711. DOI: 10.1007/s12033-023-00978-7. View

16.

Zhang C, Zhang Q, Qin L, Yan Z, Wu L, Liu T . Dioscin Ameliorates Experimental Autoimmune Thyroiditis via the mTOR and TLR4/NF-κB Signaling. Drug Des Devel Ther. 2023; 17:2273-2285. PMC: 10404412. DOI: 10.2147/DDDT.S410901. View

17.

Han S, Li X, Gan Y, Li W . Licochalcone A Promotes the Ubiquitination of c-Met to Abrogate Gefitinib Resistance. Biomed Res Int. 2022; 2022:5687832. PMC: 8930240. DOI: 10.1155/2022/5687832. View

18.

Liao J, Qing X, Deng G, Xiao Y, Fu Y, Han S . Gastrodin destabilizes survivin and overcomes pemetrexed resistance. Cell Signal. 2023; 110:110851. DOI: 10.1016/j.cellsig.2023.110851. View

19.

Gao Y, Yang Z, Ji T, Zhou P, Geng L, Gao X . Anti-papillary thyroid carcinoma effects of dioscorea bulbifera L. through ferroptosis and the PI3K/AKT pathway based on network pharmacology and experimental validation. J Ethnopharmacol. 2024; 326:117912. DOI: 10.1016/j.jep.2024.117912. View

20.

Li M, Zhao Q, Liao J, Wang X, Liu L, Zhang X . Dioscin inhibiting EGFR-mediated Survivin expression promotes apoptosis in oral squamous cell carcinoma cells. J Cancer. 2023; 14(11):2027-2038. PMC: 10367921. DOI: 10.7150/jca.85011. View