Dual STAT-3 and IL-6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL-6/IL-6R/STAT-3 axis

被引:20
|
作者
Mendez-Clemente, Anibal [1 ,2 ]
Bravo-Cuellar, Alejandro [2 ,3 ]
Gonzalez-Ochoa, Salvador [1 ,2 ]
Santiago-Mercado, Maria [2 ]
Palafox-Mariscal, Luis [1 ,2 ]
Jave-Suarez, Luis [1 ,2 ]
Solorzano-Ibarra, Fabiola [4 ]
Villasenor-Garcia, Maria [2 ,5 ]
Ortiz-Lazareno, Pablo [2 ,6 ]
Hernandez-Flores, Georgina [2 ,6 ]
机构
[1] Univ Guadalajara UdeG, Univ Ctr Hlth Sci CUCS, Doctoral Program Biomed Sci Orientat Immunol, Guadalajara 44340, Jalisco, Mexico
[2] Mexican Social Secur Inst, Western Biomed Res Ctr, Immunol Div, Guadalajara 44340, Jalisco, Mexico
[3] Univ Guadalajara UdeG, Los Altos Univ Ctr CUAltos, Dept Hlth Sci, Tepatitlan De Morelos 47620, Jalisco, Mexico
[4] Univ Guadalajara UdeG, Univ Ctr Hlth Sci CUCS, Chron Degenerat Dis Res Inst, Dept Mol & Genom Biol, Guadalajara 44340, Jalisco, Mexico
[5] Univ Ctr Exact Sci & Engn, Univ Guadalajara UdeG, Pharmacobiol Dept, Guadalajara 44340, Jalisco, Mexico
[6] Mexican Social Secur Inst, Western Biomed Res Ctr, Immunol Div, 800 Sierra Mojada, Guadalajara 44340, Jalisco, Mexico
关键词
prostate cancer; STAT-3; IL-6; receptor; clonogenicity; migration; invasion; tocilizumab; stattic; ENDOTHELIAL GROWTH-FACTOR; OVARIAN-CANCER; E-CADHERIN; INTERLEUKIN-6; INFLAMMATION; ACTIVATION; EXPRESSION; CYTOTOXICITY; ANGIOGENESIS; PATHWAY;
D O I
10.3892/or.2022.8349
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT-3, IL-6 receptor (R) and IL-6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT-3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE-1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU-145 (metastatic, castration-resistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT-3, phosphorylated STAT-3 (In-Cell Western), IL-6R, vimentin and epithelial (E-) cadherin (Western Blot). The effect of inhibition of STAT-3 (expressed constitutively in DU-145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and E-cadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL-6, C-X-C chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased E-cadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU-145 cells; addition of IL-6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL-6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT-3 inhibitor, with Tcz, an antibody against IL-6R, to target tumor cells.
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页数:16
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