期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 18, 页码 E3729-E3738出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1703096114
关键词
drug resistance; Hippo pathway; gemcitabine; cell density; cancer
资金
- NIH [R01 HD073104, R01 GM103785]
- Novartis Institutes for BioMedical Research-Harvard collaboration
- Ellison Foundation
Chemotherapy is widely used for cancer treatment, but its effectiveness is limited by drug resistance. Here, we report a mechanism by which cell density activates the Hippo pathway, which in turn inactivates YAP, leading to changes in the regulation of genes that control the intracellular concentrations of gemcitabine and several other US Food and Drug Administration (FDA)-approved oncology drugs. Hippo inactivation sensitizes a diverse panel of cell lines and human tumors to gemcitabine in 3D spheroid, mouse xenografts, and patient-derived xenograft models. Nuclear YAP enhances gemcitabine effectiveness by down-regulating multidrug transporters as well by converting gemcitabine to a less active form, both leading to its increased intracellular availability. Cancer cell lines carrying genetic aberrations that impair the Hippo signaling pathway showed heightened sensitivity to gemcitabine. These findings suggest that switching off of the Hippo-YAP pathway could help to prevent or reverse resistance to some cancer therapies.
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