mTOR 抑制消除顺铂耐药唾液腺癌干样细胞。
mTOR Inhibition Ablates Cisplatin-Resistant Salivary Gland Cancer Stem Cells.
机构信息
Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
出版信息
J Dent Res. 2021 Apr;100(4):377-386. doi: 10.1177/0022034520965141. Epub 2020 Oct 17.
Patients with advanced salivary gland mucoepidermoid carcinoma (MEC) are treated with surgery and radiotherapy, as current systemic therapies are largely ineffective. As such, current treatment frequently leads to poor long-term survival due to locoregional recurrence or metastases. We have shown that salivary gland cancer stem cells (CSCs) are resistant to platinum-based chemotherapy and drive tumor progression. The purpose of this study was to investigate the effect of therapeutic inhibition of mTOR (mechanistic target of rapamycin) on resistance of CSCs to cisplatin, a prototypic platinum-based chemotherapeutic agent. Viability assays determined the effect of several inhibitors of PI3k/mTOR signaling (e.g., temsirolimus, BKM120, AZD8055, PF4708671) and/or cisplatin on survival of human MEC cells. The impact of mTOR inhibitors and/or cisplatin on MEC stemness was examined with salisphere assays, flow cytometry for ALDH/CD44 (CSC markers for MEC), and Western blots for Bmi-1 expression (marker of stem cell self-renewal). Salivary gland MEC patient-derived xenografts were used to examine the effect of cisplatin and/or temsirolimus on CSCs in vivo. We observed that cisplatin induced mTOR and S6K1 phosphorylation, increased the number and size of MEC salispheres, and induced Bmi-1 expression and the fraction of CSCs in MEC models in vitro. Cisplatin also increased the fraction of CSCs in vivo. In contrast, mTOR inhibition (e.g., temsirolimus) blocked cisplatin-induced Bmi-1 expression and salisphere formation in vitro. Remarkably, temsirolimus slowed down tumor growth and decreased the fraction of CSCs ( < 0.05) even in presence of cisplatin in a short-term in vivo experiment. Collectively, these results demonstrate that therapeutic inhibition of mTOR ablates cytotoxic-resistant CSCs, and they suggest that a combination of an mTOR inhibitor and platinum-based chemotherapy might be beneficial to patients with salivary gland mucoepidermoid carcinoma.
患有晚期涎腺黏液表皮样癌（MEC）的患者接受手术和放疗治疗，因为目前的系统疗法在很大程度上无效。因此，由于局部复发或转移，目前的治疗方法常常导致长期生存不良。我们已经表明，涎腺癌干细胞（CSC）对铂类化疗药物具有耐药性，并促进肿瘤进展。本研究的目的是研究抑制 mTOR（雷帕霉素的作用靶点）对 CSC 对顺铂（典型的铂类化疗药物）耐药性的影响。细胞活力测定法确定了几种 PI3k/mTOR 信号通路抑制剂（例如替西罗莫司、BKM120、AZD8055、PF4708671）和顺铂对人 MEC 细胞存活的影响。通过唾液球体测定法、ALDH/CD44（MEC 的 CSC 标志物）的流式细胞术以及 Bmi-1 表达（干细胞自我更新的标志物）的 Western blot 检查 mTOR 抑制剂和/或顺铂对 MEC 干性的影响。使用涎腺癌患者来源的异种移植来检查顺铂和/或替西罗莫司对体内 CSC 的影响。我们观察到顺铂诱导 mTOR 和 S6K1 磷酸化，增加 MEC 唾液球体的数量和大小，并在体外诱导 MEC 模型中的 Bmi-1 表达和 CSC 分数。顺铂还增加了体内 CSC 的分数。相比之下，mTOR 抑制（例如替西罗莫司）阻断了体外顺铂诱导的 Bmi-1 表达和唾液球体形成。值得注意的是，替西罗莫司甚至在体内短期实验中存在顺铂的情况下，也能减缓肿瘤生长并降低 CSC 的分数（<0.05）。总的来说，这些结果表明，mTOR 的治疗性抑制消除了细胞毒性耐药性的 CSC，并表明 mTOR 抑制剂和铂类化疗药物的联合治疗可能对涎腺癌患者有益。
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