Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.
National Centre for Cancer Care and Research, Hamad Medical Corporation, Doha 3050, Qatar.
Int J Mol Sci. 2020 Jan 9;21(2):438. doi: 10.3390/ijms21020438.
The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705-STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study's findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.
Janus 激酶/信号转导子和转录激活子（JAK/STAT）信号转导的组成性激活在与甲状腺癌相关的 STAT3 介导的致癌作用中得到了很好的阐明，被认为是一个合理的治疗靶点。因此，我们研究了姜黄素（一种天然化合物）是否可以靶向 JAK/STAT3 信号通路，以诱导甲状腺乳头状癌细胞系（BCPAP 和 TPC-1）和衍生的甲状腺癌干细胞样细胞（thyrospheres）产生细胞毒性作用。姜黄素通过诱导半胱天冬酶介导的细胞凋亡，以剂量依赖的方式抑制 PTC 细胞的存活，并导致组成性激活的 STAT3（Tyr705-STAT3 的去磷酸化）减弱，而不影响 STAT3。用 STAT3 特异性 siRNA 进行基因沉默显示，与细胞生长和增殖相关的基因发生了调制。用姜黄素和顺铂共同处理 PTC 细胞系通过抑制 JAK/STAT3 活性，同时抑制抗凋亡基因和诱导促凋亡基因，协同增强了细胞毒性作用，还通过下调基质金属蛋白酶和抑制集落形成来抑制 PTC 细胞的迁移。最后，用姜黄素和顺铂处理的 thyrospheres 显示出 STAT3 磷酸化受到抑制，thyrospheres 的形成减少，以及干性标志物的表达下调，此外还有细胞凋亡。本研究的结果表明，姜黄素通过靶向 STAT3，与顺铂协同增强了 PTC 细胞以及癌干细胞样细胞的抗癌活性，这表明姜黄素与化疗药物联合使用可能会带来更好的治疗效果。
