Original Article

Cucurbitacin I inhibits STAT3, but enhances STAT1 signaling in human cancer cells in vitro through disrupting actin filaments

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Abstract

STAT1 and STAT3 are two important members of the STAT (signal transducers and activators of transcription) protein family and play opposing roles in regulating cancer cell growth. Suppressing STAT3 and/or enhancing STAT1 signaling are considered to be attractive anticancer strategies. Cucurbitacin I (CuI) isolated from the cucurbitacin family was reported to be an inhibitor of STAT3 signaling and a disruptor of actin cytoskeleton. In this study we investigated the function and mechanisms of CuI in regulating STAT signaling in human cancer cells in vitro. CuI (0.1–10 mmol/L) dose-dependently inhibited the phosphorylation of STAT3, and enhanced the phosphorylation of STAT1 in lung adenocarcinoma A549 cells possibly through disrupting actin filaments. We further demonstrated that actin filaments physically associated with JAK2 and STAT3 in A549 cells and regulated their phosphorylation through two signaling complexes, the IL-6 receptor complex and the focal adhesion complex. Actin filaments also interacted with STAT1 in A549 cells and regulated its dephosphorylation. Taken together, this study reveals the molecular mechanisms of CuI in the regulation of STAT signaling and in a possible inhibition of human cancer cell growth. More importantly, this study uncovers a novel role of actin and actin-associated signaling complexes in regulating STAT signaling.

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Acknowledgements

This work was supported by the China Ministry of Science and Technology Key New Drug Creation and Manufacturing Program (No 2014ZX9102001002 to Qiang YU), the China National Key Basic Research Program (No 2013CB910900 to Qiang YU), and the National Natural Science Foundation of China (No 81373447 and 81673465 to Qiang YU).

Author information

Affiliations

  1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

    • Hui Guo
    • , Shan Kuang
    • , Qiao-ling Song
    • , Man Liu
    • , Xiao-xiao Sun
    •  & Qiang Yu
  2. University of Chinese Academy of Sciences, Beijing 100049, China

    • Hui Guo
    • , Shan Kuang
    • , Qiao-ling Song
    • , Man Liu
    • , Xiao-xiao Sun
    •  & Qiang Yu

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Corresponding author

Correspondence to Qiang Yu.