TY  - JOUR
A1  - Jüngel, Eva
A1  - Natsheh, Iyad Y. M.
A1  - Najafi, Ramin
A1  - Rutz, Jochen
A1  - Tsaur, Igor
A1  - Haferkamp, Axel
A1  - Chun, Felix
A1  - Blaheta, Roman A.
T1  - Mechanisms behind temsirolimus resistance causing reactivated growth and invasive behavior of bladder cancer cells in vitro
T2  - Cancers
N2  - Background: Although mechanistic target of rapamycin (mTOR) inhibitors, such as temsirolimus, show promise in treating bladder cancer, acquired resistance often hampers efficacy. This study evaluates mechanisms leading to resistance. Methods: Cell growth, proliferation, cell cycle phases, and cell cycle regulating proteins were compared in temsirolimus resistant (res) and sensitive (parental—par) RT112 and UMUC3 bladder cancer cells. To evaluate invasive behavior, adhesion to vascular endothelium or to immobilized extracellular matrix proteins and chemotactic activity were examined. Integrin α and β subtypes were analyzed and blocking was done to evaluate physiologic integrin relevance. Results: Growth of RT112res could no longer be restrained by temsirolimus and was even enhanced in UMUC3res, accompanied by accumulation in the S- and G2/M-phase. Proteins of the cdk-cyclin and Akt-mTOR axis increased, whereas p19, p27, p53, and p73 decreased in resistant cells treated with low-dosed temsirolimus. Chemotactic activity of RT112res/UMUC3res was elevated following temsirolimus re-exposure, along with significant integrin α2, α3, and β1 alterations. Blocking revealed a functional switch of the integrins, driving the resistant cells from being adhesive to being highly motile. Conclusion: Temsirolimus resistance is associated with reactivation of bladder cancer growth and invasive behavior. The α2, α3, and β1 integrins could be attractive treatment targets to hinder temsirolimus resistance.
KW  - bladder cancer
KW  - mechanistic target of rapamycin (mTOR)
KW  - temsirolimus-resistance
KW  - growth
KW  - invasion
KW  - integrins
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51505
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-515058
SN  - 2072-6694
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
VL  - 11
IS  - 6, Art. 777
SP  - 1
EP  - 22
PB  - MDPI
CY  - Basel
ER  -