Lycorine suppressed oral squamous cell carcinoma cell proliferation and invasion via scap protein degradation: an experimental study

doi:10.19438/j.cjoms.2024.01.005

Abstract

Abstract: PURPOSE: To investigate the effects of Lycorine, a natural plant extract, on oral squamous cell carcinoma (OSCC) cells and its underlying mechanisms. METHODS: Plate cloning assay and flow cytometry were used to evaluate the inhibitory effect of Lycorine on the proliferation of OSCC in vitro. Scratch assay and Transwell assay were conducted to assess the impact of Lycorine on the invasion of OSCC. Western blot and immunofluorescence were performed to confirm the inhibitory effect of Lycorine on SCAP protein in OSCC. A nude mouse xenograft model was established to evaluate the in vivo anticancer effect of Lycorine against oral squamous cell carcinoma. Graphpad Prism software package was used for statistical analysis. RESULTS: Plate cloning assay and flow cytometry showed that Lycorine significantly inhibited the proliferation of OSCC cells in vitro. Scratch assay and Transwell assay revealed a significant inhibitory effect of Lycorine on the migration and invasion of OSCC cells. Western blot and immunofluorescence results demonstrated that Lycorine could degrade SCAP protein in OSCC cells, affecting cholesterol metabolism in cancer cells. Animal experiment results further indicated that Lycorine exhibited potent anticancer activity in vivo, significantly suppressing the growth of OSCC cells and reducing the levels of SCAP protein within cancer cells. CONCLUSIONS: Lycorine can suppress the proliferation and invasion of OSCC cells by degrading SCAP protein, making it a potential low-toxicity and highly effective natural plant extract for the prevention and treatment of OSCC.

Key words: Lycorine, Oral squamous cell carcinoma, SREBP cleavage activating protein, Proliferation, Invasion

CLC Number:

R739.8

LI Hua-sheng, ZHOU Di, HAN Nan-nan, YAN Ming, RUAN Min. Lycorine suppressed oral squamous cell carcinoma cell proliferation and invasion via scap protein degradation: an experimental study[J]. China Journal of Oral and Maxillofacial Surgery, 2024, 22(1): 29-35.

References

[1] Johnson DE, Burtness B, Leemans CR, et al.Head and neck squamous cell carcinoma[J]. Nat Rev Dis Primers, 2020, 6(1): 92-140.
[2] Chow LQM.Head and neck cancer[J]. N Engl J Med, 2020, 382(1): 60-72.
[3] Siegel RL, Miller KD, Jemal A.Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30.
[4] Caudell JJ, Gillison ML, Maghami E, et al.NCCN Guidelines^® Insights: Head and Neck Cancers, Version 1.2022[J]. J Natl Compr Canc Netw, 2022,20(3):224-234.
[5] Ettinger KS, Ganry L, Fernandes RP.Oral cavity cancer[J]. Oral Maxillofac Surg Clin North Am, 2019, 31(1): 13-29.
[6] Burtness B, Harrington KJ, Greil R, et al.Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck(KEYNOTE-048): a randomised, open-label, phase 3 study[J]. Lancet, 2019, 394(10212): 1915-1928.
[7] Ferris RL, Blumenschein G, Fayette J, et al.Nivolumab for recurrent squamous-cell carcinoma of the head and neck[J]. N Engl J Med, 2016, 375(19): 1856-1867.
[8] Cohen EEW, Soulières D, Le Tourneau C, et al.Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study[J]. Lancet, 2019, 393(10167): 156-167.
[9] Schoenfeld JD, Hanna GJ, Jo VY, et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial[J]. JAMA Oncol, 2020, 6(10): 1563-1570.
[10] Zou W, Wolchok JD, Chen L. PD-L1(B7-H1) andPD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers,combinations [J]. Sci Transl Med, 2016, 8(328): 328rv4.
[11] Zheng ZG, Zhu ST, Cheng HM, et al.Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway[J]. Autophagy, 2021, 17(7): 1592-1613.
[12] Roy M, Liang L, Xiao X, et al.Lycorine: a prospective natural lead for anticancer drug discovery[J]. Biomed Pharmacother, 2018, 107: 615-624.
[13] Cedrón JC, Gutiérrez D, Flores N, et al.Synthesis and antiplasmodial activity of lycorine derivatives[J]. Bioorg Med Chem, 2010, 18(13): 4694-4701.
[14] Locárek M, Nováková J, Kloucek P, et al.Antifungal and antibacterial activity of extracts and alkaloids of selected amaryllidaceae species[J]. Nat Prod Commun, 2015, 10(9): 1537-1540.
[15] Lamoral-theys D, Andolfi A, Van Goietsenoven G, et al. Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight[J]. J Med Chem, 2009, 52(20): 6244-6256.
[16] Roy M, Liang L, Xiao X, et al.Lycorine downregulates HMGB1 to inhibit autophagy and enhances bortezomib activity in multiple myeloma[J]. Theranostics, 2016, 6(12): 2209-2224.
[17] Kang J, Zhang Y, Cao X, et al.Lycorine inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in RAW264.7 cells through suppressing P38 and STATs activation and increases the survival rate of mice after LPS challenge[J]. Int Immunopharmacol, 2012, 12(1): 249-256.
[18] Horton JD, Goldstein JL, Brown MS.SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver[J]. J Clin Invest, 2002, 109(9): 1125-1131.
[19] Van Meer G, Voelker DR, Feigenson GW.Membrane lipids: where they are and how they behave[J]. Nat Rev Mol Cell Biol, 2008, 9(2): 112-124.
[20] Brown MS, Goldstein JL.The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor[J]. Cell, 1997, 89(3): 331-340.
[21] Horton JD, Shah NA, Warrington JA, et al.Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes[J]. Proc Natl Acad Sci U S A, 2003, 100(21): 12027-12032.
[22] Radhakrishnan A, Goldstein JL, Mcdonald JG, et al.Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance[J]. Cell Metab, 2008, 8(6): 512-521.
[23] Brown MS, Goldstein JL.A receptor-mediated pathway for cholesterol homeostasis[J]. Science, 1986, 232(4746): 34-47.
[24] Ikonen E.Cellular cholesterol trafficking and compartmentalization[J]. Nat Rev Mol Cell Biol, 2008, 9(2): 125-138.
[25] Tasdogan A, Faubert B, Ramesh V, et al.Metabolic heterogeneity confers differences in melanoma metastatic potential[J]. Nature, 2020, 577(7788): 115-120.
[26] Cai D, Wang J, Gao B, et al.RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype[J]. Nat Commun, 2019, 10(1): 4621.
[27] Pelton K, Freeman MR, Solomon KR.Cholesterol and prostate cancer[J]. Curr Opin Pharmacol, 2012, 12(6): 751-759.
[28] Shafique K, Mcloone P, Qureshi K, et al.Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up[J]. BMC Cancer, 2012, 12: 25-33.
[29] Tao M, Luo J, Gu T, et al.LPCAT1 reprogramming cholesterol metabolism promotes the progression of esophageal squamous cell carcinoma[J]. Cell Death Dis, 2021, 12(9): 845-859.
[30] Lewis CA, Brault C, Peck B, et al.SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme[J]. Oncogene, 2015, 34(40): 5128-5140.
[31] Huang B, Song BL, Xu C.Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities[J]. Nat Metab, 2020, 2(2): 132-141.