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Nafamostat mesilate negatively regulates the metastasis of triple-negative breast cancer cells
Sunam Mander,유동주,박수미,김동휘,용효정,김동식,Curie Ahn,김윤희,성재영,황종익 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.2
Triple-negative breast cancer (TNBC) lacking ofoestrogen receptor, progesterone receptor, and epidermalgrowth factor receptor type 2 is a highly malignant diseasewhich results in a poor prognosis and rare treatmentoptions. Despite the use of conventional chemotherapy forTNBC tumours, resistance and short duration responseslimit the treatment efficacy. Therefore, a need exists todevelop a new chemotherapy for TNBC. The aim of thisstudy was to examine the anti-cancer effects of nafamostatmesilate (NM), a previously known serine protease inhibitorand highly safe drug on breast cancer cells. Here, weshowed that NM significantly inhibits proliferation,migration, and invasion in MDA-MB231 cells, induces G2/M phase cell-cycle arrest, and inhibits the expression ofcyclin-dependent kinase 1 (CDK1). Exposure of MDAMB231cells to NM also resulted in decreased transcriptionfactor activities accompanied by the regulated phosphorylationof signalling molecules and a decrease in metalloproteinases,the principal modulators of the extracellularenvironment during cancer progression. Especially, inhibitionof TGFb-stimulated Smad2 phosphorylation andsubsequent metastasis-related gene expression, and downregulationof ERK activity may be pivotal mechanismsunderlying inhibitory effects of NM on NM inhibits lungmetastasis of breast cancer cells and growth of colonizedtumours in mice. Taken together, our data revealed thatNM inhibits cell growth and metastasis of TNBC cells andindicated that NM is a multi-targeted drug that could be anadjunct therapy for TNBC treatment.
( Dong Hwi Kim ),( Hyo Jeong Yong ),( Sunam Mander ),( Huong Thi Nguyen ),( Lan Phuong Nguyen ),( Hee-kyung Park ),( Hyo Kyeong Cha ),( Won-ki Kim ),( Jong-ik Hwang ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.3
Liver cancer is a common tumor and currently the second leading cause of cancer-related mortality globally. Liver cancer is highly related to inflammation as more than 90% of liver cancer arises in the context of hepatic inflammation, such as hepatitis B virus and hepatitis C virus infection. Despite significant improvements in the therapeutic modalities for liver cancer, patient prognosis is not satisfactory due to the limited efficacy of current drug therapies in anti-metastatic activity. Therefore, developing new effective anti-cancer agents with anti-metastatic activity is important for the treatment of liver cancer. In this study, SP-8356, a verbenone derivative with anti-inflammatory activity, was investigated for its effect on the growth and migration of liver cancer cells. Our findings demonstrated that SP-8356 inhibits the proliferation of liver cancer cells by inducing apoptosis and suppressing the mobility and invasion ability of liver cancer cells. Functional studies revealed that SP-8356 inhibits the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways, which are related to cell proliferation and metastasis, resulting in the downregulation of metastasis-related genes. Moreover, using an orthotopic liver cancer model, tumor growth was significantly decreased following treatment with SP-8356. Thus, this study suggests that SP-8356 may be a potential agent for the treatment of liver cancer with multimodal regulation.
Characterization of Functional Domains in NME1L Regulation of NF-κB Signaling
You, Dong-Joo,Park, Cho Rong,Mander, Sunam,Ahn, Curie,Seong, Jae Young,Hwang, Jong-Ik Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.5
NME1 is a well-known metastasis suppressor which has been reported to be downregulated in some highly aggressive cancer cells. Although most studies have focused on NME1, the NME1 gene also encodes the protein (NME1L) containing N-terminal 25 extra amino acids by alternative splicing. According to previous studies, NME1L has potent anti-metastatic activity, in comparison with NME1, by interacting with $IKK{\beta}$ and regulating its activity. In the present study, we tried to define the role of the N-terminal 25 amino acids of NME1L in $NF-{\kappa}B$ activation signaling. Unfortunately, the sequence itself did not interact with $IKK{\beta}$, suggesting that it may be not enough to constitute the functional structure. Further construction of NME1L fragments and biochemical analysis revealed that N-terminal 84 residues constitute minimal structure for homodimerization, $IKK{\beta}$ interaction and regulation of $NF-{\kappa}B$ signaling. The inhibitory effect of the fragment on cancer cell migration and $NF-{\kappa}B$-stimulated gene expression was equivalent to that of whole NME1L. The data suggest that the N-terminal 84 residues may be a core region for the anti-metastatic activity of NME1L. Based on this result, further structural analysis of the binding between NME1L and $IKK{\beta}$ may help in understanding the anti-metastatic activity of NME1L and provide direction to NME1L and $IKK{\beta}$-related anti-cancer drug design.
Characterization of Functional Domains in NME1L Regulation of NF-kappaB Signaling
Jong-Ik Hwang,Dong-Joo You,Cho Rong Park,Sunam Mander,Curie Ahn,Jae Young Seong 한국분자세포생물학회 2016 Molecules and cells Vol.39 No.5
NME1 is a well-known metastasis suppressor which has been reported to be downregulated in some highly ag-gressive cancer cells. Although most studies have fo-cused on NME1, the NME1 gene also encodes the protein (NME1L) containing N-terminal 25 extra amino acids by alternative splicing. According to previous studies, NME1L has potent anti-metastatic activity, in comparison with NME1, by interacting with IKKbeta and regulating its activity. In the present study, we tried to define the role of the N-terminal 25 amino acids of NME1L in NF-kappaB activation signaling. Unfortunately, the sequence itself did not interact with IKKbeta, suggesting that it may be not enough to constitute the functional structure. Further construction of NME1L fragments and biochemical analysis revealed that N-terminal 84 residues constitute minimal structure for homodimerization, IKKbeta interaction and regulation of NF-kappaB signaling. The inhibitory effect of the fragment on cancer cell migration and NF-kappaB-stimulated gene expression was equivalent to that of whole NME1L. The data suggest that the N-terminal 84 residues may be a core region for the anti-metastatic activity of NME1L. Based on this result, further structural analysis of the binding between NME1L and IKKbeta may help in understanding the anti-metastatic activity of NME1L and provide direction to NME1L and IKKbeta-related anti-cancer drug design.