Downregulation of Hyaluronic Acid-CD44 Signaling Pathway in Cervical Cancer Cell by Natural Polyphenols Plumbagin, Pongapin and Karanjin

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2021 Jun 3

PMID 34081254

Citations 11

Authors

Rituparna Roy

Suvra Mandal

Jayanta Chakrabarti

Prosenjit Saha

Chinmay Kumar Panda

Affiliations

Soon will be listed here.

Abstract

Hyaluronic acid (HA)-CD44 pathway showed association with several malignancies. The natural polyphenols Plumbagin, Pongapin and Karanjin showed anti-cancer activities in different tumors including cervical carcinoma. To understand their mechanism of anti-cancer activity, the effect of the compounds on HA-CD44 pathway was analyzed in cervical cancer cell line HeLa. The mRNA expression of three different isoforms of CD44 i.e., CD44s, CD44v3, and CD44v6, was differentially downregulated by the compounds. This was validated by Western blot and immunocytochemical analysis of CD44s.The low molecular weight HA (LMW-HA) showed growth promoting activity in HeLa at low concentration, whereas high molecular weight HA (HMW-HA) had no such effect. The compounds could preferentially downregulate the LMW-HA level in HeLa, as evident in the cell as well as in the cell-free conditioned medium. Concentration-dependent upregulation of HA synthase-2 (HAS2) was seen in the cell by the compounds, whereas differential downregulation of hyalurinidases 1-4 (HYAL 1-4), predominantly HYAL1, were seen. The compounds could also downregulate the downstream target of the pathway p-AKT (T-308) in concentration-dependent manner. Thus, the compounds could attenuate the HA-CD44 pathway in HeLa cell to restrict the tumor growth.

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References

Chen C, Zhao S, Karnad A, Freeman J . The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol. 2018; 11(1):64. PMC: 5946470. DOI: 10.1186/s13045-018-0605-5. View

Toole B, Slomiany M . Hyaluronan, CD44 and Emmprin: partners in cancer cell chemoresistance. Drug Resist Updat. 2008; 11(3):110-21. PMC: 2584579. DOI: 10.1016/j.drup.2008.04.002. View

Toole B . Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004; 4(7):528-39. DOI: 10.1038/nrc1391. View

Bourguignon L . Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol. 2008; 18(4):251-9. PMC: 2505114. DOI: 10.1016/j.semcancer.2008.03.007. View

Rivas S, Gomez-Oro C, Anton I, Wandosell F . Role of Akt Isoforms Controlling Cancer Stem Cell Survival, Phenotype and Self-Renewal. Biomedicines. 2018; 6(1). PMC: 5874686. DOI: 10.3390/biomedicines6010029. View

Bahmad H, Mouhieddine T, Chalhoub R, Assi S, Araji T, Chamaa F . The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma. Oncotarget. 2018; 9(71):33549-33561. PMC: 6173359. DOI: 10.18632/oncotarget.26088. View

Ponta H, Sherman L, Herrlich P . CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003; 4(1):33-45. DOI: 10.1038/nrm1004. View

Baykal C, Al A, Ayhan A . Altered CD44 variant 6 expression in FIGO stage IB cervical carcinoma. Gynecol Oncol. 2001; 83(3):569-74. DOI: 10.1006/gyno.2001.6406. View

Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J . High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013; 499(7458):346-9. PMC: 3720720. DOI: 10.1038/nature12234. View

10.

Weigel P, DeAngelis P . Hyaluronan synthases: a decade-plus of novel glycosyltransferases. J Biol Chem. 2007; 282(51):36777-81. DOI: 10.1074/jbc.R700036200. View

11.

Moretto P, Karousou E, Viola M, Caon I, DAngelo M, De Luca G . Regulation of hyaluronan synthesis in vascular diseases and diabetes. J Diabetes Res. 2015; 2015:167283. PMC: 4365328. DOI: 10.1155/2015/167283. View

12.

Tavianatou A, Caon I, Franchi M, Piperigkou Z, Galesso D, Karamanos N . Hyaluronan: molecular size-dependent signaling and biological functions in inflammation and cancer. FEBS J. 2019; 286(15):2883-2908. DOI: 10.1111/febs.14777. View

13.

Gupta R, Lall R, Srivastava A, Sinha A . Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory. Front Vet Sci. 2019; 6:192. PMC: 6603175. DOI: 10.3389/fvets.2019.00192. View

14.

Roy R, Pal D, Sur S, Mandal S, Saha P, Panda C . Pongapin and Karanjin, furanoflavanoids of Pongamia pinnata, induce G2/M arrest and apoptosis in cervical cancer cells by differential reactive oxygen species modulation, DNA damage, and nuclear factor kappa-light-chain-enhancer of activated B cell.... Phytother Res. 2019; 33(4):1084-1094. DOI: 10.1002/ptr.6302. View

15.

Amado N, Predes D, Moreno M, Carvalho I, Mendes F, Abreu J . Flavonoids and Wnt/β-catenin signaling: potential role in colorectal cancer therapies. Int J Mol Sci. 2014; 15(7):12094-106. PMC: 4139831. DOI: 10.3390/ijms150712094. View

16.

Xue Y, Meng X, Ma L, Yuan Z . Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling. Oncol Lett. 2016; 12(2):1095-1100. PMC: 4950492. DOI: 10.3892/ol.2016.4725. View

17.

Dasgupta H, Islam M, Alam N, Roy A, Roychoudhury S, Panda C . Induction of HRR genes and inhibition of DNMT1 is associated with anthracycline anti-tumor antibiotic-tolerant breast carcinoma cells. Mol Cell Biochem. 2018; 453(1-2):163-178. DOI: 10.1007/s11010-018-3442-5. View

18.

Cowman M, Chen C, Pandya M, Yuan H, Ramkishun D, LoBello J . Improved agarose gel electrophoresis method and molecular mass calculation for high molecular mass hyaluronan. Anal Biochem. 2011; 417(1):50-6. DOI: 10.1016/j.ab.2011.05.023. View

19.

Bhilocha S, Amin R, Pandya M, Yuan H, Tank M, LoBello J . Agarose and polyacrylamide gel electrophoresis methods for molecular mass analysis of 5- to 500-kDa hyaluronan. Anal Biochem. 2011; 417(1):41-9. PMC: 3207642. DOI: 10.1016/j.ab.2011.05.026. View

20.

Bourguignon L . Matrix Hyaluronan-CD44 Interaction Activates MicroRNA and LncRNA Signaling Associated With Chemoresistance, Invasion, and Tumor Progression. Front Oncol. 2019; 9:492. PMC: 6598393. DOI: 10.3389/fonc.2019.00492. View