Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey.
Department of Medical Biology, Faculty of Medicine, Giresun University, Giresun, 28100, Turkey.
Mol Biol Rep. 2022 Nov;49(11):10387-10397. doi: 10.1007/s11033-022-07751-0. Epub 2022 Sep 12.
FoxM1 transcription factor contributes to tumor metastasis and poor prognosis in many cancers including triple-negative breast cancer (TNBC). In this study, we examined the effects of FoxM1 inhibitor Thiostrepton (THIO) alone or in combination with MEK inhibitor Selumetinib (SEL) on metastatic parameters in vitro and in vivo.
Cell viability was determined by MTT assay. Immunoblotting and immunohistochemistry was used to assess metastasis-related protein expressions in 4T1 cells and its allograft tumor model in BALB/c mice. In vivo uPA activity was determined by enzymatic methods.
Both inhibitors were effective on the expressions of FoxM1, ERK, p-ERK, Twist, E-cadherin, and Vimentin alone or in combination in vitro. THIO significantly decreased 4T1 cell migration and changed the cell morphology from mesenchymal-like to epithelial-like structure. THIO was more effective than in combination with SEL in terms of metastatic protein expressions in vivo. THIO alone significantly inhibited mean tumor growth, decreased lung metastasis rate and tumor foci, however, no significant changes in these parameters were observed in the combined group. Immunohistochemically, FoxM1 expression intensity was decreased with THIO and its combination with SEL in the tumors.
This study suggests that inhibiting FoxM1 as a single target is more effective than combined treatment with MEK in theTNBC allograft model. The therapeutic efficacy of THIO should be investigated with further studies on appropriate drug delivery systems.
FoxM1 转录因子在包括三阴性乳腺癌（TNBC）在内的许多癌症中促进肿瘤转移和预后不良。在这项研究中，我们研究了 FoxM1 抑制剂硫链丝菌素（THIO）单独或与 MEK 抑制剂 Selumetinib（SEL）联合应用对体外和体内转移参数的影响。
通过 MTT 测定法测定细胞活力。免疫印迹和免疫组织化学用于评估 4T1 细胞及其在 BALB/c 小鼠中的同种异体肿瘤模型中的转移相关蛋白表达。通过酶法测定体内 uPA 活性。
两种抑制剂均能有效抑制 FoxM1、ERK、p-ERK、Twist、E-cadherin 和 Vimentin 的表达，无论是单独使用还是联合使用，均能有效抑制 FoxM1、ERK、p-ERK、Twist、E-cadherin 和 Vimentin 的表达。THIO 显著降低了 4T1 细胞的迁移能力，并使细胞形态从间充质样转变为上皮样结构。THIO 单独使用在体内对转移蛋白表达的抑制作用优于与 SEL 联合使用。THIO 单独使用可显著抑制平均肿瘤生长，降低肺转移率和肿瘤灶，但联合组这些参数无明显变化。免疫组化结果显示，FoxM1 表达强度随 THIO 及其与 SEL 的联合应用而降低。
本研究表明，抑制 FoxM1 作为单一靶点比联合使用 MEK 在 TNBC 同种异体移植模型中更有效。THIO 的治疗效果应通过进一步研究适当的药物输送系统进行研究。
