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2017 ; 114
(18
): E3729-E3738
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Hippo pathway mediates resistance to cytotoxic drugs
#MMPMID28416665
Gujral TS
; Kirschner MW
Proc Natl Acad Sci U S A
2017[May]; 114
(18
): E3729-E3738
PMID28416665
show ga
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.
|Adaptor Proteins, Signal Transducing/genetics/metabolism
[MESH]
free
free
free
