PMID- 31167517
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 11
IP  - 6
DP  - 2019 Jun 4
TI  - Mechanisms behind Temsirolimus Resistance Causing Reactivated Growth and Invasive 
      Behavior of Bladder Cancer Cells In Vitro.
LID - 10.3390/cancers11060777 [doi]
LID - 777
AB  - 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 alpha and beta 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 alpha2, alpha3, and beta1 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 alpha2, alpha3, and beta1 
      integrins could be attractive treatment targets to hinder temsirolimus 
      resistance.
FAU - Juengel, Eva
AU  - Juengel E
AD  - Department of Urology, Goethe University Hospital, 60590 Frankfurt am Main, 
      Germany. eva.juengel@unimedizin-mainz.de.
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      Langenbeckstr. 1, 55131 Mainz, Germany. eva.juengel@unimedizin-mainz.de.
FAU - Natsheh, Iyad
AU  - Natsheh I
AUID- ORCID: 0000-0002-8121-7281
AD  - Department of Allied Medical Sciences, Zarqa University College, Al-Balqa Applied 
      University, Salt 13110, Jordan. iyadnatsheh@bau.edu.jo.
FAU - Najafi, Ramin
AU  - Najafi R
AD  - Department of Urology, Goethe University Hospital, 60590 Frankfurt am Main, 
      Germany. ramin_n@hotmail.de.
FAU - Rutz, Jochen
AU  - Rutz J
AD  - Department of Urology, Goethe University Hospital, 60590 Frankfurt am Main, 
      Germany. Jochen.Rutz@kgu.de.
FAU - Tsaur, Igor
AU  - Tsaur I
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      Langenbeckstr. 1, 55131 Mainz, Germany. igor.tsaur@unimedizin-mainz.de.
FAU - Haferkamp, Axel
AU  - Haferkamp A
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      Langenbeckstr. 1, 55131 Mainz, Germany. axel.haferkamp@unimedizin-mainz.de.
FAU - Chun, Felix K-H
AU  - Chun FK
AD  - Department of Urology, Goethe University Hospital, 60590 Frankfurt am Main, 
      Germany. Felix.Chun@kgu.de.
FAU - Blaheta, Roman A
AU  - Blaheta RA
AD  - Department of Urology, Goethe University Hospital, 60590 Frankfurt am Main, 
      Germany. blaheta@em.uni-frankfurt.de.
LA  - eng
PT  - Journal Article
DEP - 20190604
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC6627393
OTO - NOTNLM
OT  - bladder cancer
OT  - growth
OT  - integrins
OT  - invasion
OT  - mechanistic target of rapamycin (mTOR)
OT  - temsirolimus-resistance
COIS- The authors declare no conflicts of interest.
EDAT- 2019/06/07 06:00
MHDA- 2019/06/07 06:01
PMCR- 2019/06/04
CRDT- 2019/06/07 06:00
PHST- 2019/05/21 00:00 [received]
PHST- 2019/05/27 00:00 [revised]
PHST- 2019/05/28 00:00 [accepted]
PHST- 2019/06/07 06:00 [entrez]
PHST- 2019/06/07 06:00 [pubmed]
PHST- 2019/06/07 06:01 [medline]
PHST- 2019/06/04 00:00 [pmc-release]
AID - cancers11060777 [pii]
AID - cancers-11-00777 [pii]
AID - 10.3390/cancers11060777 [doi]
PST - epublish
SO  - Cancers (Basel). 2019 Jun 4;11(6):777. doi: 10.3390/cancers11060777.