A Novel Synthetic Oleanane Triterpenoid Suppresses Adhesion, Migration, and Invasion of Highly Metastatic Melanoma Cells by Modulating Gelatinase Signaling Axis

Overview

Journal Mol Carcinog

Specialties Molecular Biology
Oncology

Date 2014 Feb 11

PMID 24510625

Citations 2

Authors

Dona Sinha

Kaustav Dutta

Kirat K Ganguly

Jaydip Biswas

Anupam Bishayee

Affiliations

Soon will be listed here.

Abstract

A methyl derivative natural triterpenoid amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) has been found to possess antiproliferative, proapoptotic, and antiinflammatory effects against established tumor cells. Large-scale synthesis of pure AMR-Me has eliminated the need of the natural phytochemical for further development of AMR-Me as an anticancer drug. Metastatic melanoma is a fatal form of cutaneous malignancy with poor prognosis and limited therapeutic options. It was hypothesized that antitumor pharmacological effect of AMR-Me could be linked to AMR-Me-mediated suppression of the metastatic potential of B16F10 murine melanoma. AMR-Me was assessed for its antimetastatic efficacy by cell adhesion, migration, and invasion assays in B16F10 cells. The signaling crosstalk was explored by gelatin zymography, Western blot, ELISA, and immunocytochemistry. The results elicited that AMR-Me was successful in restricting the adhesion, migration, and invasion of highly metastatic cells. The antimetastatic potential of this compound may be attributed to the reduced expression of membrane type 1 metalloproteinase (MT1-MMP) and matrix metalloproteinases (MMP-2 and MMP-9). AMR-Me was found to downregulate vascular endothelial growth factor (VEGF)/phosphorylated forms of focal adhesion kinase (pFAK397 )/Jun N-terminus kinase (pJNK)/extracellular signal-regulated kinase (pERK). This, in turn, inhibited transcription factor nuclear factor-κB (NF-κB) and transactivation of MMPs. Moreover, the activation of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) might have influenced the downmodulation of MT1-MMP, MMP-2, and MMP-9. AMR-Me suppresses the activity of MT1-MMP, MMP-2, and MMP-9 by downregulation of VEGF/pFAK397 /pJNK/pERK/NF-κB and activation of TIMP-1 and TIMP-2 in metastatic melanoma cell line, B16F10. AMR-Me has the potential as an effective anticancer drug for metastatic melanoma which is a dismal disease.

Citing Articles

Complex Inhibitory Activity of Pentacyclic Triterpenoids against Cutaneous Melanoma In Vitro and In Vivo: A Literature Review and Reconstruction of Their Melanoma-Related Protein Interactome.

Moralev A, Zenkova M, Markov A ACS Pharmacol Transl Sci. 2024; 7(11):3358-3384.

PMID: 39539268 PMC: 11555519. DOI: 10.1021/acsptsci.4c00422.

Cirsiliol Suppressed Epithelial to Mesenchymal Transition in B16F10 Malignant Melanoma Cells through Alteration of the PI3K/Akt/NF-κB Signaling Pathway.

Prasad P, Vasas A, Hohmann J, Bishayee A, Sinha D Int J Mol Sci. 2019; 20(3).

PMID: 30708951 PMC: 6386903. DOI: 10.3390/ijms20030608.

References

Thoppil R, Bishayee A . Terpenoids as potential chemopreventive and therapeutic agents in liver cancer. World J Hepatol. 2011; 3(9):228-49. PMC: 3182282. DOI: 10.4254/wjh.v3.i9.228. View

Han S, Ritzenthaler J, Sitaraman S, Roman J . Fibronectin increases matrix metalloproteinase 9 expression through activation of c-Fos via extracellular-regulated kinase and phosphatidylinositol 3-kinase pathways in human lung carcinoma cells. J Biol Chem. 2006; 281(40):29614-24. DOI: 10.1074/jbc.M604013200. View

Rabi T, Banerjee S . Novel synthetic triterpenoid methyl 25-hydroxy-3-oxoolean-12-en-28-oate induces apoptosis through JNK and p38 MAPK pathways in human breast adenocarcinoma MCF-7 cells. Mol Carcinog. 2007; 47(6):415-23. DOI: 10.1002/mc.20399. View

Rabi T, Ramachandran C, Fonseca H, Nair R, Alamo A, Melnick S . Novel drug amooranin induces apoptosis through caspase activity in human breast carcinoma cell lines. Breast Cancer Res Treat. 2003; 80(3):321-30. DOI: 10.1023/A:1024911925623. View

Suh N, Wang Y, Honda T, Gribble G, Dmitrovsky E, Hickey W . A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res. 1999; 59(2):336-41. View

Chase A, Bond M, Crook M, Newby A . Role of nuclear factor-kappa B activation in metalloproteinase-1, -3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo. Arterioscler Thromb Vasc Biol. 2002; 22(5):765-71. DOI: 10.1161/01.atv.0000015078.09208.92. View

Bishayee A, Mandal A, Thoppil R, Darvesh A, Bhatia D . Chemopreventive effect of a novel oleanane triterpenoid in a chemically induced rodent model of breast cancer. Int J Cancer. 2013; 133(5):1054-63. PMC: 3702660. DOI: 10.1002/ijc.28108. View

Takino T, Nakada M, Miyamori H, Watanabe Y, Sato T, Gantulga D . JSAP1/JIP3 cooperates with focal adhesion kinase to regulate c-Jun N-terminal kinase and cell migration. J Biol Chem. 2005; 280(45):37772-81. DOI: 10.1074/jbc.M505241200. View

Shishodia S, Sethi G, Konopleva M, Andreeff M, Aggarwal B . A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin Cancer Res. 2006; 12(6):1828-38. DOI: 10.1158/1078-0432.CCR-05-2044. View

10.

Al-Hazmi N, Thomas G, Speight P, Whawell S . The 120 kDa cell-binding fragment of fibronectin up-regulates migration of alphavbeta6-expressing cells by increasing matrix metalloproteinase-2 and -9 secretion. Eur J Oral Sci. 2007; 115(6):454-8. DOI: 10.1111/j.1600-0722.2007.00481.x. View

11.

Qin Y, Deng W, Ekmekcioglu S, Grimm E . Identification of unique sensitizing targets for anti-inflammatory CDDO-Me in metastatic melanoma by a large-scale synthetic lethal RNAi screening. Pigment Cell Melanoma Res. 2012; 26(1):97-112. PMC: 3919534. DOI: 10.1111/pcmr.12031. View

12.

Guruvayoorappan C, Kuttan G . Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, STAT-1, NM23 and cytokines in lung tissues of C57BL/6 mice. Immunopharmacol Immunotoxicol. 2008; 30(4):711-27. DOI: 10.1080/08923970802278276. View

13.

Jin Y, Park I, Hong I, Byun H, Choi J, Kim Y . Fibronectin and vitronectin induce AP-1-mediated matrix metalloproteinase-9 expression through integrin α(5)β(1)/α(v)β(3)-dependent Akt, ERK and JNK signaling pathways in human umbilical vein endothelial cells. Cell Signal. 2010; 23(1):125-34. DOI: 10.1016/j.cellsig.2010.08.012. View

14.

Das S, Banerji A, Frei E, Chatterjee A . Rapid expression and activation of MMP-2 and MMP-9 upon exposure of human breast cancer cells (MCF-7) to fibronectin in serum free medium. Life Sci. 2008; 82(9-10):467-76. DOI: 10.1016/j.lfs.2007.12.013. View

15.

Cox B, Natarajan M, Stettner M, Gladson C . New concepts regarding focal adhesion kinase promotion of cell migration and proliferation. J Cell Biochem. 2006; 99(1):35-52. DOI: 10.1002/jcb.20956. View

16.

Jutooru I, Chadalapaka G, Abdelrahim M, Basha M, Samudio I, Konopleva M . Methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol Pharmacol. 2010; 78(2):226-36. PMC: 2917860. DOI: 10.1124/mol.110.064451. View

17.

Geiger B, Bershadsky A, Pankov R, Yamada K . Transmembrane crosstalk between the extracellular matrix--cytoskeleton crosstalk. Nat Rev Mol Cell Biol. 2001; 2(11):793-805. DOI: 10.1038/35099066. View

18.

Tran K, Risingsong R, Royce D, Williams C, Sporn M, Liby K . The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice. Cancer Prev Res (Phila). 2012; 5(5):726-34. DOI: 10.1158/1940-6207.CAPR-11-0404. View

19.

Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E . A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994; 370(6484):61-5. DOI: 10.1038/370061a0. View

20.

Bishayee A, Ahmed S, Brankov N, Perloff M . Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Front Biosci (Landmark Ed). 2011; 16(3):980-96. PMC: 3057757. DOI: 10.2741/3730. View