Inhibition of NF-kB/IL-6/JAK2/STAT3 Pathway and Epithelial-Mesenchymal Transition in Breast Cancer Cells by Azilsartan

被引:31
作者
Alaaeldin, Rania [1 ]
Ali, Fares E. M. [2 ]
Bekhit, Amany Abdlrehim [3 ]
Zhao, Qing-Li [4 ]
Fathy, Moustafa [3 ,5 ]
机构
[1] Deraya Univ, Fac Pharm, Dept Biochem, Al Minya 61111, Egypt
[2] Al Azhar Univ, Fac Pharm, Dept Pharmacol & Toxicol, Assiut Branch, Assiut 71524, Egypt
[3] Minia Univ, Fac Pharm, Dept Biochem, Al Minya 61519, Egypt
[4] Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Radiol, Toyama 9300194, Japan
[5] Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Regenerat Med, Toyama 9300194, Japan
关键词
azilsartan; breast cancer; NF-kB; EMT; IL-6; JAK2; STAT3; SLUG; TWIST; SNAIL; NF-KAPPA-B; HEPATOCELLULAR-CARCINOMA; APOPTOSIS; RECEPTOR; EMT; COMBINATIONS; INFLAMMATION; MODULATION; MIGRATION; SLUG;
D O I
10.3390/molecules27227825
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Metastatic breast cancer is an incurable form of breast cancer that exhibits high levels of epithelial-mesenchymal transition (EMT) markers. Angiotensin II has been linked to various signaling pathways involved in tumor cell growth and metastasis. The aim of this study is to investigate, for the first time, the anti-proliferative activity of azilsartan, an angiotensin II receptor blocker, against breast cancer cell lines MCF-7 and MDA-MB-231 at the molecular level. Cell viability, cell cycle, apoptosis, colony formation, and cell migration assays were performed. RT-PCR and western blotting analysis were used to explain the molecular mechanism. Azilsartan significantly decreased the cancer cells survival, induced apoptosis and cell cycle arrest, and inhibited colony formation and cell migration abilities. Furthermore, azilsartan reduced the mRNA levels of NF-kB, TWIST, SNAIL, SLUG and bcl2, and increased the mRNA level of bax. Additionally, azilsartan inhibited the expression of IL-6, JAK2, STAT3, MMP9 and bcl2 proteins, and increased the expression of bax, c-PARP and cleaved caspase 3 protein. Interestingly, it reduced the in vivo metastatic capacity of MDA-MBA-231 breast cancer cells. In conclusion, the present study revealed, for the first time, the anti-proliferative, apoptotic, anti-migration and EMT inhibition activities of azilsartan against breast cancer cells through modulating NF-kB/IL-6/JAK2/STAT3/MMP9, TWIST/SNAIL/SLUG and apoptosis signaling pathways.
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页数:19
相关论文
共 71 条
[11]   Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers [J].
Alves, Catarina Castro ;
Carneiro, Fatima ;
Hoefler, Heinz ;
Becker, Karl-Friedrich .
FRONTIERS IN BIOSCIENCE-LANDMARK, 2009, 14 :3041-3050
[12]   Gastroprotective Effect of Azilsartan Through Ameliorating Oxidative Stress, Inflammation, and Restoring Hydroxyproline, and Gastrin Levels in Ethanol-Induced Gastric Ulcer [J].
Amin, Renas Raouf Hama ;
Aziz, Tavga Ahmed .
JOURNAL OF INFLAMMATION RESEARCH, 2022, 15 :2911-2923
[13]   Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence [J].
Balko, Justin M. ;
Schwarz, Luis J. ;
Luo, Na ;
Estrada, Monica V. ;
Giltnane, Jennifer M. ;
Davila-Gonzalez, Daniel ;
Wang, Kai ;
Sanchez, Violeta ;
Dean, Phillip T. ;
Combs, Susan E. ;
Hicks, Donna ;
Pinto, Joseph A. ;
Landis, Melissa D. ;
Doimi, Franco D. ;
Yelensky, Roman ;
Miller, Vincent A. ;
Stephens, Phillip J. ;
Rimm, David L. ;
Gomez, Henry ;
Chang, Jenny C. ;
Sanders, Melinda E. ;
Cook, Rebecca S. ;
Arteaga, Carlos L. .
SCIENCE TRANSLATIONAL MEDICINE, 2016, 8 (334)
[14]   GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues [J].
Barber, RD ;
Harmer, DW ;
Coleman, RA ;
Clark, BJ .
PHYSIOLOGICAL GENOMICS, 2005, 21 (03) :389-395
[15]   A "class action" against the microenvironment: do cancer cells cooperate in metastasis? [J].
Bidard, Francois-Clement ;
Pierga, Jean-Yves ;
Vincent-Salomon, Anne ;
Poupon, Marie-France .
CANCER AND METASTASIS REVIEWS, 2008, 27 (01) :5-10
[16]   The relevance of EMT in breast cancer metastasis: Correlation or causality? [J].
Bill, Ruben ;
Christofori, Gerhard .
FEBS LETTERS, 2015, 589 (14) :1577-1587
[17]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[18]   Genistein inhibits NF-κB activation in prostate cancer cells [J].
Davis, JN ;
Kucuk, O ;
Sarkar, FH .
NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL, 1999, 35 (02) :167-174
[19]   Angiotensin receptors: a new role in cancer? [J].
Deshayes, F ;
Nahmias, C .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2005, 16 (07) :293-299
[20]  
Eisa M.A., 2021, Minia J. Med. Res., V32, P47