Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation
Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation
复制标题
伊曲康唑诱导的对人食管癌细胞生长的抑制需要 AMPK 激活。
DOI：
10.1158/1535-7163.mct-17-1094
复制
发表时间：
2018-06-01
影响因子：
5.7
通讯作者：
Cao, Cong
中科院分区：
文献类型：
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作者：
Chen, Min-Bin;Liu, Yuan-Yuan;Cao, Cong
我们在这里评价抗真菌药物伊曲康唑抗食管癌细胞的活性。我们的研究结果表明，mg/mL浓度的伊曲康唑有效地抑制了已建立的（TE-1和Eca-109）和原代人食管癌细胞的存活和增殖。伊曲康唑激活AMPK信号传导，这是随后的食管癌细胞死亡所必需的。药理学AMPK抑制、AMPKa 1 shRNA或显性负突变（T172 A）几乎完全消除了伊曲康唑诱导的对食管癌细胞的细胞毒性。值得注意的是，伊曲康唑诱导AMPK依赖性自噬细胞死亡（但不是凋亡）在食管癌细胞。此外，伊曲康唑激活AMPK可诱导多种受体酪氨酸激酶（RTK：EGFR、PDGFRa和PDGFRb）、溶酶体易位和降解，从而抑制下游Akt激活。在体内，伊曲康唑经口灌胃可有效抑制SCID小鼠Eca-109肿瘤生长。它对表达AMPKa 1 shRNA的Eca-109肿瘤无效。伊曲康唑对人食管癌原代细胞的体内生长也有明显的抑制作用。在伊曲康唑处理的肿瘤中观察到AMPK活化、RTK降解和Akt抑制。总之，伊曲康唑通过激活AMPK信号传导抑制食管癌细胞生长。(C)2018年AACR。
We here evaluated the antiesophageal cancer cell activity by the antifungal drug itraconazole. Our results show that mg/mL concentrations of itraconazole potently inhibited survival and proliferation of established (TE-1 and Eca-109) and primary human esophageal cancer cells. Itraconazole activated AMPK signaling, which was required for subsequent esophageal cancer cell death. Pharmacologic AMPK inhibition, AMPKa1 shRNA, or dominant negative mutation (T172A) almost completely abolished itraconazole-induced cytotoxicity against esophageal cancer cells. Significantly, itraconazole induced AMPK-dependent autophagic cell death (but not apoptosis) in esophageal cancer cells. Furthermore, AMPK activation by itraconazole induced multiple receptor tyrosine kinases (RTKs: EGFR, PDGFRa, and PDGFRb), lysosomal translocation, and degradation to inhibit downstream Akt activation. In vivo, itraconazole oral gavage potently inhibited Eca-109 tumor growth in SCID mice. It was yet ineffective against AMPKa1 shRNA-expressing Eca-109 tumors. The in vivo growth of the primary human esophageal cancer cells was also significantly inhibited by itraconazole administration. AMPK activation, RTK degradation, and Akt inhibition were observed in itraconazole-treated tumors. Together, itraconazole inhibits esophageal cancer cell growth via activating AMPK signaling. (C) 2018 AACR.