Doctoral Program in Biomedical Sciences Orientation Immunology, University Center for Health Sciences (CUCS), University of Guadalajara (UdeG), Guadalajara, Jalisco 44340, México.
Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, México.
Oncol Rep. 2022 Aug;48(2). doi: 10.3892/or.2022.8349. Epub 2022 Jun 15.
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 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.
前列腺癌（PCa）是全球范围内的一个主要公共卫生问题；在诊断时，很大一部分患者表现出肿瘤细胞侵袭邻近组织。STAT-3、白细胞介素-6 受体（R）和白细胞介素-6 血清水平与增强的 PCa 迁移、侵袭、克隆形成和转移能力相关。在不同水平（细胞因子、受体和激酶）抑制 STAT-3 途径在癌症治疗中取得了相对成功。本研究调查了 Stattic（Stt）+托珠单抗（Tcz）对人转移性 PCa 增殖、克隆形成、迁移和侵袭能力的影响（通过集落形成、划痕愈合和迁移试验评估）。RWPE-1（前列腺上皮永生化细胞）、22Rv1（肿瘤细胞）、LNCaP（转移性细胞）和 DU-145（转移性、去势抵抗性前列腺细胞）细胞用于评估细胞因子、趋化因子、生长因子（流式细胞术 bead 阵列）、STAT-3、磷酸化 STAT-3（In-Cell Western）、IL-6R、波形蛋白和上皮（E）钙粘蛋白（Western Blot）水平。抑制 STAT-3（在 DU-145 细胞中表达为组成型）的效果通过 Stt 和/或 Tcz 对转移性 PCa 细胞中波形蛋白、VEGF 和 E-钙粘蛋白的表达水平以及增殖、克隆形成、迁移和侵袭能力的影响进行了评估。转移性 PCa 细胞中 IL-6、C-X-C 趋化因子配体 8、VEGF 和波形蛋白的表达水平以及增殖和迁移增加。Sttt 或 Tcz 治疗降低了波形蛋白和 VEGF 的表达水平，增加了 E-钙粘蛋白的表达水平，并抑制了 DU-145 细胞的增殖、克隆形成、迁移和侵袭能力；添加 IL-6 降低了这种抑制作用。然而，即使在存在高浓度 IL-6 的情况下，Stt + Tcz 仍能维持抑制作用。Stt + Tcz 降低了转移性 PCa 细胞中波形蛋白和 VEGF 的表达水平，并抑制了其增殖、克隆形成、迁移和侵袭能力。据我们所知，本研究首次将 STAT-3 抑制剂 Stt 与针对 IL-6R 的抗体 Tcz 结合，以靶向肿瘤细胞。
