The designed NF‑κB inhibitor, DHMEQ, inhibits KISS1R‑mediated invasion and increases drug‑sensitivity in mouse plasmacytoma SP2/0 cells

Lin,Yinzhi; Sidthipong,Kulrawee; Ma,Jun; Koide,Naoki; Umezawa,Kazuo; Kubota,Tetsuo

doi:10.3892/etm.2021.10526

The designed NF‑κB inhibitor, DHMEQ, inhibits KISS1R‑mediated invasion and increases drug‑sensitivity in mouse plasmacytoma SP2/0 cells

Authors:
- Yinzhi Lin
- Kulrawee Sidthipong
- Jun Ma
- Naoki Koide
- Kazuo Umezawa
- Tetsuo Kubota
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Affiliations: Department of Molecular Target Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi 480‑1195, Japan, Department of Research and Development, Shenzhen Wanhe Pharmaceutical Co., Ltd., Shenzhen, Guangdong 518107, P.R. China, Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480‑1195, Japan, Department of Microbiology and Immunology, Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo 113‑8510, Japan
Published online on: August 2, 2021 https://doi.org/10.3892/etm.2021.10526
Article Number: 1092
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Plasmacytoma is one of the most difficult types of leukemia to treat, and it often invades the bone down to the marrow resulting in the development of multiple myeloma. NF‑κB is often constitutively activated, and promotes metastasis and drug resistance in neoplastic cells. The present study assessed the cellular anticancer activity of an NF‑κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on mouse plasmacytoma SP2/0 cells. Cellular invasion was measured by Matrigel chamber assay, and apoptosis was assessed by detecting caspase‑3 cleavage and by flow cytometric analysis with Annexin V. DHMEQ inhibited constitutively activated NF‑κB at nontoxic concentrations. DHMEQ was also shown to inhibit cellular invasion of SP2/0 cells, as well as human myeloma KMS‑11 and RPMI‑8226 cells. The metastasis PCR array indicated that DHMEQ induced a decrease in KISS1 receptor (KISS1R) expression in SP2/0 cells. Knockdown of KISS1R by small interfering RNA suppressed cellular invasion, suggesting that KISS1R may serve an essential role in the invasion of SP2/0 cells. Furthermore, DHMEQ enhanced cytotoxicity of the anticancer agent melphalan in SP2/0 cells. Notably, DHMEQ inhibited the expression of NF‑κB‑dependent anti‑apoptotic proteins, such as Bcl‑XL, FLIP, and Bfl‑1. In conclusion, inhibition of constitutively activated NF‑κB by DHMEQ may be useful for future anti‑metastatic and anticancer strategies for the treatment of plasmacytoma.

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1	Dimopoulos MA, Moulopoulos LA, Maniatis A and Alexanian R: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood. 96:2037–2044. 2000.PubMed/NCBI
2	Laubach J, Richardson P and Anderson K: Multiple Myeloma. Annu Rev Med. 62:249–264. 2011.PubMed/NCBI View Article : Google Scholar
3	Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KGC, Dörner T and Hiepe F: Competence and competition: The challenge of becoming a long-lived plasma cell. Nat Rev Immunol. 6:741–750. 2006.PubMed/NCBI View Article : Google Scholar
4	Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X, Jia X, Wright R, Ospina B, Carlson AL, et al: CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood. 113:4341–4351. 2009.PubMed/NCBI View Article : Google Scholar
5	Mead EJ, Maguire JJ, Kuc RE and Davenport AP: Kisspeptins: A multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. Br J Pharmacol. 151:1143–1153. 2007.PubMed/NCBI View Article : Google Scholar
6	Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Poul EL, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, et al: The metastasis suppressor Gene KiSS-1 encodes Kisspeptins, the natural ligands of the orphan g protein-coupled receptor GPR54. J Biol Chem. 276:34631–34636. 2001.PubMed/NCBI View Article : Google Scholar
7	Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE and Welch DR: KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 88:1731–1737. 1996.PubMed/NCBI View Article : Google Scholar
8	Takeda T, Kikuchi E, Mikami S, Suzuki E, Matsumoto K, Miyajima A, Okada Y and Oya M: Prognostic role of KiSS-1 and possibility of therapeutic modality of metastin, the final peptide of the KiSS-1 gene, in urothelial carcinoma. Mol Cancer Ther. 11:853–863. 2012.PubMed/NCBI View Article : Google Scholar
9	Zhu C, Takasu C, Morine Y, Bando Y, Ikemoto T, Saito Y, Yamada S, Imura S, Arakawa Y and Shimada M: KISS1 associates with better outcome via inhibiting matrix metalloproteinase-9 in colorectal liver metastasis. Ann Surg Oncol. 22:1516–1523. 2015.PubMed/NCBI View Article : Google Scholar
10	Jiang Y, Berk M, Singh LS, Tan H, Yin L, Powell CT and Xu Y: KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clin Exp Metastasis. 22:369–376. 2005.PubMed/NCBI View Article : Google Scholar
11	Wang H, Jones J, Turner T, He QP, Hardy S, Grizzle WE, Welch DR and Yates C: Clinical and biological significance of KISS1 expression in prostate cancer. Am J Pathol. 180:1170–1178. 2012.PubMed/NCBI View Article : Google Scholar
12	Blake A, Dragan M, Tirona RG, Hardy DB, Brackstone M, Tuck AB, Babwah AV and Bhattacharya M: G protein-coupled KISS1 receptor is overexpressed in triple negative breast cancer and promotes drug resistance. Sci Rep. 7(46525)2017.PubMed/NCBI View Article : Google Scholar
13	Schmid K, Wang X, Haitel A, Sieghart W, Peck-Radosavljevic M, Bodingbauer M, Rasoul-Rockenschaub S and Wrba F: KiSS-1 overexpression as an independent prognostic marker in hepatocellular carcinoma: An immunohistochemical study. Virchows Archiv. 450:143–149. 2007.PubMed/NCBI View Article : Google Scholar
14	Rajkumar SV: Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 88:226–235. 2013.PubMed/NCBI View Article : Google Scholar
15	Hideshima T, Richardson P and Anderson KC: Novel therapeutic approaches for multiple myeloma. Immunolol Rev. 194:164–176. 2003.PubMed/NCBI View Article : Google Scholar
16	Gay F and Palumbo A: Management of disease- and treatment-related complications in patients with multiple myeloma. Med Oncol. 27:43–52. 2010.PubMed/NCBI View Article : Google Scholar
17	Mahindra A, Laubach J, Raje N, Munshi N, Richardson PG and Anderson K: Latest advances and current challenges in the treatment of multiple myeloma. Nat Rev Clin Oncol. 9:135–143. 2012.PubMed/NCBI View Article : Google Scholar
18	Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Wier SV, Tiedemann R, Shi CX, Sebag M, et al: Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 12:131–144. 2007.PubMed/NCBI View Article : Google Scholar
19	Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, et al: Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 12:115–130. 2007.PubMed/NCBI View Article : Google Scholar
20	Berenson JR, Ma HM and Vescio R: The role of nuclear factor-kappaB in the biology and treatment of multiple myeloma. Semin Oncol. 28:626–633. 2001.PubMed/NCBI View Article : Google Scholar
21	Landowski TH, Olashaw NE, Agrawal D and Dalton WS: Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells. Oncogene. 22:2417–2421. 2003.PubMed/NCBI View Article : Google Scholar
22	Umezawa K: Possible role of peritoneal NF-κB in peripheral inflammation and cancer: Lessons from the inhibitor NF-κB (Review). Biomed Pharmacother. 65:252–259. 2011.PubMed/NCBI View Article : Google Scholar
23	Tatetsu H, Okuno Y, Nakamura M, Matsuno F, Sonoki T, Taniguchi I, Uneda S, Umezawa K, Mitsuya H and Hata H: Dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappa B inhibitor, induces apoptosis in multiple myeloma cells in an IkappaBalpha-independent manner. Mol Cancer Ther. 4:1114–1120. 2005.PubMed/NCBI View Article : Google Scholar
24	Horie R, Watanabe M, Okamura T, Taira M, Shoda M, Motoji T, Utsunomiya A, Watanabe T, Higashihara M and Umezawa K: DHMEQ, a new NF-kappaB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells. Leukemia. 20:800–806. 2006.PubMed/NCBI View Article : Google Scholar
25	Suzuki Y, Sugiyama C, Ohno O and Umezawa K: Preparation and biological activities of optically active dehydroxymethylepoxyquinomicin, a novel NF-κB inhibitor. Tetrahedron. 60:7061–7066. 2004.
26	Ni H, Ergin M, Huang Q, Qin JZ, Amin HM, Martinez RL, Saeed S, Barton K and Alkan S: Analysis of expression of nuclear factor B (NF-kappa B) in multiple myeloma: Down-regulation of NF-kappa B induces apoptosis. Br J Haematol. 115:279–286. 2001.PubMed/NCBI View Article : Google Scholar
27	Barkette M and Gilmore TD: Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene. 18:6910–6924. 1999.PubMed/NCBI View Article : Google Scholar
28	Pahl HL: Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 18:6853–6866. 1999.PubMed/NCBI View Article : Google Scholar
29	Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Miguel JF, et al: Safety and efficacy of bortezomib in high risk and elderly patients with relapsed multiple myeloma. Br J Haematol. 137:429–435. 2007.PubMed/NCBI View Article : Google Scholar
30	Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR, Jaye DL, Francis D, Giusti S, Torre C, et al: Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 106:3777–3784. 2005.PubMed/NCBI View Article : Google Scholar
31	Yamamoto M, Horie R, Takeiri M, Kozawa I and Umezawa K: Inactivation of NF-kappaB components by covalent binding of (-)-dehydroxymethylepoxyquinomicin to specific cysteine residues. J Med Chem. 51:5780–5788. 2008.PubMed/NCBI View Article : Google Scholar
32	Vega MI, Martinez-Paniagua M, Jazirehi AR, Huerta-Yepez S, Umezawa K, Martinez-Maza O and Bonavida B: The NF-kappaB inhibitors (bortezomib and DHMEQ) sensitise rituximab-resistant AIDS-B-non-Hodgkin lymphoma to apoptosis by various chemotherapeutic drugs. Leuk Lymphoma. 49:1982–1994. 2008.PubMed/NCBI View Article : Google Scholar
33	Ando Y, Sato Y, Kudo A, Watanabe T, Hirakata A, Okada AA, Umezawa K and Keino H: Anti-inflammatory effects of the NF-κB inhibitor dehydroxymethylepoxyquinomicin on ARPE-19 cells. Mol Med Rep. 22:582–590. 2020.PubMed/NCBI View Article : Google Scholar