WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis.
WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis.
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WZB117通过阻断STAT3/PKM2轴增强阿帕替尼对黑色素瘤的抗肿瘤作用
DOI：
10.3389/fphar.2022.976117
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发表时间：
2022
影响因子：
5.6
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Zhang RS;Li ZK;Liu J;Deng YT;Jiang Y
背景资料：黑色素瘤是最致命的皮肤恶性肿瘤，一旦进入转移状态，生存期短，给治疗带来挑战。阿帕替尼（一种酪氨酸激酶抑制剂）是治疗转移性黑色素瘤的一种很有前途的抗血管生成剂。然而，抗血管生成单药治疗容易产生获得性耐药性，治疗效果有限。糖酵解代谢在抗血管生成治疗抗性细胞中的持续依赖性提供了糖酵解抑制剂可以增强抗血管生成治疗效果的证据。因此，本研究旨在探讨特异性GLUT 1抑制剂WZB 117能否增强阿帕替尼对黑色素瘤的抗肿瘤作用及其可能机制。 方法：我们研究了阿帕替尼单独或与WZB 117联合对人黑色素瘤细胞系（A375和SK-MEL-28）的抗肿瘤作用。MTT法测定细胞活力和半数最大抑制浓度（IC 50）。进行了多药物效应/联合指数（CI）分析，以评估阿帕替尼与WZB 117之间的相互作用。通过蛋白质印迹和免疫荧光染色测量信号转导子和转录激活子3（STAT 3）途径。使用逆转录-定量PCR方法进行RNA表达分析。 结果：阿帕替尼和WZB 117对两种黑色素瘤细胞均表现出剂量和时间依赖性的生长抑制作用。阿帕替尼在A375和SK-MEL-28细胞中48 h的IC 50分别为62.58和59.61 μM，而WZB 117的IC 50分别为116.85和113.91 μM。两种药物的CI值分别为0.538和0.544，表明阿帕替尼联合WZB 117具有协同作用。我们还发现，阿帕替尼加WZB 117以剂量依赖性方式抑制葡萄糖消耗和乳酸产生，这主要是通过减少糖酵解酶丙酮酸激酶M2（PKM 2）实现的。联合应用的潜在机制是抑制STAT 3的磷酸化。siRNA敲除STAT 3可抑制PKM 2的表达，IL-6激活STAT 3可促进PKM 2的表达。阿帕替尼联合WZB 117治疗可减弱IL-6的作用。 结论：WZB 117通过阻断STAT 3/PKM 2轴调节糖酵解增强阿帕替尼对黑色素瘤的抗肿瘤作用，这表明阿帕替尼与WZB 117的组合可能是黑色素瘤的潜在治疗候选物。
Background: Melanoma is the most lethal skin malignant tumor with a short survival once stepping into the metastatic status and poses a therapeutic challenge. Apatinib (a tyrosine kinase inhibitor) is a promising antiangiogenic agent for the treatment of metastatic melanoma. However, antiangiogenic monotherapy is prone to acquired drug resistance and has a limited therapeutic effect. The persistence dependence of glycolytic metabolism in antiangiogenic therapy-resistant cells provides evidence that glycolysis inhibitors may enhance the effect of antiangiogenic therapy. So, this study aimed to investigate whether WZB117 (a specific GLUT1 inhibitor) could enhance the anti-tumor effect of apatinib against melanoma and its potential mechanisms. Methods: We investigated the anti-tumor effects of apatinib alone or in combination with WZB117 on human melanoma cell lines (A375 and SK-MEL-28). The MTT assay determined cell viability and the half-maximal inhibitory concentration (IC50). Multiple drug effect/combination indexes (CI) analysis was conducted to assess interactions between apatinib and WZB117. Signal transducer and activator of transcription 3 (STAT3) pathway measured by western blotting and immunofluorescence staining. RNA expression analyses were performed using the reverse transcription-quantitative PCR method. Results: Apatinib and WZB117 showed dose and time-dependent growth inhibitory effects in both melanoma cells. The IC50 of apatinib at 48 h in A375 and SK-MEL-28 cells was 62.58 and 59.61 μM, respectively, while the IC50 of WZB117 was 116.85 and 113.91 μM, respectively. The CI values of the two drugs were 0.538 and 0.544, respectively, indicating a synergistic effect of apatinib combined with WZB117. We also found that glucose consumption and lactate production were suppressed by apatinib plus WZB117 in a dose-dependent manner, paralleled by reducing glycolytic enzyme pyruvate kinase M2 (PKM2). The potential mechanism of the combination was to suppress the phosphorylation of STAT3. Knockdown of STAT3 by siRNA inhibited the expression of PKM2, while the activation of STAT3 by IL-6 increased the expression of PKM2. The effects of IL-6 were attenuated by apatinib combined with WZB117 treatment. Conclusion: WZB117 enhanced the anti-tumor effect of apatinib against melanoma via modulating glycolysis by blocking the STAT3/PKM2 axis, which suggested the combination of apatinib with WZB117 could be a potential therapeutic candidate for melanoma.
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影响因子：
13.8
作者：
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通讯作者：
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影响因子：
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通讯作者：
Markovic, Svetomir N.
影响因子：
9
作者：
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