American Association for Cancer Research
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Figure S3 from Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation

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posted on 2023-04-03, 16:10 authored by Min-Bin Chen, Yuan-Yuan Liu, Zhao-Yu Xing, Zhi-Qing Zhang, Qin Jiang, Pei-Hua Lu, Cong Cao

Figure S3. Stable Eca-109 cells (5Ã-106 cells per mouse), expressing scramble control shRNA ("shRNA-C") or AMPKα1 shRNA ("sh-AMPKα1"), were inoculated (s.c. injection) to the SCID mice, with 8 mice per group. When the volume of each tumor was around 150 mm3 ("D0"), the recording started. The tumor volume (A) and the mice body weight (D) were recorded every 7 days; Daily tumor growth (in mm3 per day) was calculated (B); At day-42, tumors were separated and weighted (C). At experimental Day-8, one Eca-109 tumor per group was isolated, expression of listed proteins were tested by a Western blotting assay (E).

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National Natural Science Foundation

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ARTICLE ABSTRACT

We here evaluated the antiesophageal cancer cell activity by the antifungal drug itraconazole. Our results show that μg/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, AMPKα1 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, PDGFRα, and PDGFRβ), 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 AMPKα1 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. Mol Cancer Ther; 17(6); 1229–39. ©2018 AACR.

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