FLI-06 Intercepts Notch Signaling And Suppresses The Proliferation And Self-renewal Of Tongue Cancer Cells

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2019 Oct 2

PMID 31571917

Citations 6

Authors

Rui-Huan Gan

Li-Song Lin

Jing Xie

Li Huang

Lin-Can Ding

Bo-Hua Su

Xian-E Peng

Da-Li Zheng

You-Guang Lu

Affiliations

Soon will be listed here.

Abstract

Purpose: The Notch signaling pathway plays an oncogenic role in tongue squamous cell carcinoma. The aim of this study was to inhibit the proliferation and self-renewal of tongue cancer cells by applying Notch signaling pathway inhibitor FLI-06 (Selleck, USA) and to lay a foundation for the clinically targeted treatment of tongue cancer for the future.

Methods: The mRNA expression level of Notch1 and the overall survival rate of patients with tongue cancer were examined by analyzing the TCGA database. Tongue cancer cells were treated with FLI-06. Cell proliferation, apoptosis, and stem cell self-renewal ability were tested in appropriate ways. A xenograft mouse model was established to observe tumor growth.

Results: From the TCGA data, we demonstrated that patients with high expression of Notch1 had a poor prognosis. We observed that the Notch signaling pathway inhibitor FLI-06 can restrain the activation of the Notch signaling pathway, decrease cell proliferation and induce cell apoptosis in vitro. The xenograft experiment indicated that intraperitoneal injection of FLI-06 inhibited tumor growth and increased cell apoptosis. FLI-06 suppressed both the mRNA and protein expression of Notch receptor and Notch targeted genes. We also observed that FLI-06 suppressed the proliferation of tongue cancer stem cells.

Conclusion: FLI-06 can block the proliferation and self-renewal of tongue cancer cells. It is inferred that this compound, which inhibits the Notch signaling pathway, may serve as a potential targeted drug for the treatment of tongue cancer in the clinic.

Citing Articles

Modulation of Notch Signaling by Small-Molecular Compounds and Its Potential in Anticancer Studies.

Czerwonka A, Kalafut J, Nees M Cancers (Basel). 2023; 15(18).

PMID: 37760535 PMC: 10526229. DOI: 10.3390/cancers15184563.

Oral squamous cell carcinomas: state of the field and emerging directions.

Tan Y, Wang Z, Xu M, Li B, Huang Z, Qin S Int J Oral Sci. 2023; 15(1):44.

PMID: 37736748 PMC: 10517027. DOI: 10.1038/s41368-023-00249-w.

Notch signaling, hypoxia, and cancer.

Guo M, Niu Y, Xie M, Liu X, Li X Front Oncol. 2023; 13:1078768.

PMID: 36798826 PMC: 9927648. DOI: 10.3389/fonc.2023.1078768.

Notch signaling in the pathogenesis, progression and identification of potential targets for cholangiocarcinoma (Review).

Vanaroj P, Chaijaroenkul W, Na-Bangchang K Mol Clin Oncol. 2022; 16(3):66.

PMID: 35154706 PMC: 8825743. DOI: 10.3892/mco.2022.2499.

Comprehending the crosstalk between Notch, Wnt and Hedgehog signaling pathways in oral squamous cell carcinoma - clinical implications.

Patni A, Harishankar M, Joseph J, Sreeshma B, Jayaraj R, Devi A Cell Oncol (Dordr). 2021; 44(3):473-494.

PMID: 33704672 DOI: 10.1007/s13402-021-00591-3.

References

Wang Z, Da Silva T, Jin K, Han X, Ranganathan P, Zhu X . Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. Cancer Res. 2014; 74(21):6364-74. PMC: 4527315. DOI: 10.1158/0008-5472.CAN-14-2051. View

Schott A, Landis M, Dontu G, Griffith K, Layman R, Krop I . Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res. 2013; 19(6):1512-24. PMC: 3602220. DOI: 10.1158/1078-0432.CCR-11-3326. View

Yonemura Y, Li X, Muller K, Kramer A, Atigbire P, Mentrup T . Inhibition of cargo export at ER exit sites and the trans-Golgi network by the secretion inhibitor FLI-06. J Cell Sci. 2016; 129(20):3868-3877. DOI: 10.1242/jcs.186163. View

Gan R, Wei H, Xie J, Zheng D, Luo E, Huang X . Notch1 regulates tongue cancer cells proliferation, apoptosis and invasion. Cell Cycle. 2017; 17(2):216-224. PMC: 5884382. DOI: 10.1080/15384101.2017.1395534. View

Ng J, Iyer N, Tan M, Edgren G . Changing epidemiology of oral squamous cell carcinoma of the tongue: A global study. Head Neck. 2016; 39(2):297-304. DOI: 10.1002/hed.24589. View

Panaccione A, Chang M, Carbone B, Guo Y, Moskaluk C, Virk R . NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma. Clin Cancer Res. 2016; 22(8):2083-95. PMC: 4834904. DOI: 10.1158/1078-0432.CCR-15-2208. View

Zhang J, Kuang Y, Wang Y, Xu Q, Ren Q . Notch-4 silencing inhibits prostate cancer growth and EMT via the NF-κB pathway. Apoptosis. 2017; 22(6):877-884. DOI: 10.1007/s10495-017-1368-0. View

Hu J, Zhu X, Lu Q . Antiproliferative effects of γ-secretase inhibitor, a Notch signalling inhibitor, in multiple myeloma cells and its molecular mechanism of action. J Int Med Res. 2013; 41(4):1017-26. DOI: 10.1177/0300060513485912. View

Lu Z, Ren Y, Zhang M, Fan T, Wang Y, Zhao Q . FLI-06 suppresses proliferation, induces apoptosis and cell cycle arrest by targeting LSD1 and Notch pathway in esophageal squamous cell carcinoma cells. Biomed Pharmacother. 2018; 107:1370-1376. DOI: 10.1016/j.biopha.2018.08.140. View

10.

Nyman P, Buehler D, Lambert P . Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis. Clin Cancer Res. 2018; 24(24):6308-6318. PMC: 6295262. DOI: 10.1158/1078-0432.CCR-17-3535. View

11.

Giachino C, Boulay J, Ivanek R, Alvarado A, Tostado C, Lugert S . A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes. Cancer Cell. 2015; 28(6):730-742. DOI: 10.1016/j.ccell.2015.10.008. View

12.

Fortini M . Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol. 2002; 3(9):673-84. DOI: 10.1038/nrm910. View

13.

Gomez-Galeno J, Hurtado C, Cheng J, Yardimci C, Mercola M, Cashman J . b-Annulated 1,4-dihydropyridines as Notch inhibitors. Bioorg Med Chem Lett. 2018; 28(20):3363-3367. PMC: 6261437. DOI: 10.1016/j.bmcl.2018.09.002. View

14.

Hayashi T, Gust K, Wyatt A, Goriki A, Jager W, Awrey S . Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy. Clin Cancer Res. 2016; 22(12):2981-92. DOI: 10.1158/1078-0432.CCR-15-2360. View

15.

Dawood S, Austin L, Cristofanilli M . Cancer stem cells: implications for cancer therapy. Oncology (Williston Park). 2014; 28(12):1101-7, 1110. View

16.

Natsuizaka M, Whelan K, Kagawa S, Tanaka K, Giroux V, Chandramouleeswaran P . Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat Commun. 2017; 8(1):1758. PMC: 5700926. DOI: 10.1038/s41467-017-01500-9. View

17.

Aster J, Pear W, Blacklow S . The Varied Roles of Notch in Cancer. Annu Rev Pathol. 2016; 12:245-275. PMC: 5933931. DOI: 10.1146/annurev-pathol-052016-100127. View

18.

Ghantous Y, Abu Elnaaj I . [GLOBAL INCIDENCE AND RISK FACTORS OF ORAL CANCER]. Harefuah. 2017; 156(10):645-649. View

19.

Qu J, Song M, Xie J, Huang X, Hu X, Gan R . Notch2 signaling contributes to cell growth, invasion, and migration in salivary adenoid cystic carcinoma. Mol Cell Biochem. 2015; 411(1-2):135-41. DOI: 10.1007/s11010-015-2575-z. View

20.

Kovall R, Gebelein B, Sprinzak D, Kopan R . The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force. Dev Cell. 2017; 41(3):228-241. PMC: 5492985. DOI: 10.1016/j.devcel.2017.04.001. View