PMID- 24862756
OWN - NLM
STAT- MEDLINE
DCOM- 20150123
LR  - 20211203
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 16
IP  - 4
DP  - 2014 Apr
TI  - Resistance to the mTOR inhibitor temsirolimus alters adhesion and migration 
      behavior of renal cell carcinoma cells through an integrin alpha5- and integrin 
      beta3-dependent mechanism.
PG  - 291-300
LID - S1476-5586(14)00030-X [pii]
LID - 10.1016/j.neo.2014.03.011 [doi]
AB  - Inhibitors of the mammalian target of rapamycin (mTOR) have improved the 
      treatment of renal cell carcinoma (RCC). However, chronic drug exposure may 
      trigger resistance, limiting the utility of these agents. The metastatic behavior 
      of RCC cells, susceptible (RCC(par)) or resistant (RCC(res)) to the mTOR 
      inhibitor temsirolimus, was investigated. Adhesion to vascular endothelium or 
      immobilized collagen and fibronectin was quantified. Chemotactic motility was 
      evaluated with a modified Boyden chamber assay. Integrin alpha and beta subtype 
      receptors were analyzed by flow cytometry and Western blot analysis. The 
      physiological relevance of the integrins was then determined by blocking studies 
      and small interfering RNA knockdown. Adhesion to endothelial cells and to 
      fibronectin (not to collagen) and chemotaxis were enhanced in RCC(res) compared 
      to RCC(par). RCC(res) detached from fibronectin and motile activity further 
      increased under retreatment with low-dosed temsirolimus. alpha5 integrin was 
      diminished inside the cell and at the cell surface, whereas the beta3 subtype was 
      reduced intracellularly but elevated at the plasma membrane. In RCC(par), 
      blocking alpha5 surface receptors enhanced RCC-collagen but reduced RCC-fibronectin 
      interaction, whereas the opposite was true for RCC(res). Chemotaxis of RCC(par) 
      but not of RCC(res) was strongly diminished by the alpha5 antibody. Blocking beta3 
      significantly lowered chemotaxis with stronger effects on RCC(res), compared to 
      RCC(par). Importantly, beta3 knockdown reduced chemotaxis of RCC(par) but 
      upregulated the motile behavior of RCC(res). Temsirolimus resistance is 
      characterized by quantitative alterations of integrin alpha5 and beta3 expression, 
      coupled to functional changes of the integrin molecules, and forces a switch from 
      RCC adhesion to RCC migration.
CI  - Copyright (c) 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights 
      reserved.
FAU - Juengel, Eva
AU  - Juengel E
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany.
FAU - Makarevic, Jasmina
AU  - Makarevic J
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany.
FAU - Reiter, Michael
AU  - Reiter M
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany.
FAU - Mani, Jens
AU  - Mani J
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany.
FAU - Tsaur, Igor
AU  - Tsaur I
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany.
FAU - Bartsch, Georg
AU  - Bartsch G
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany.
FAU - Haferkamp, Axel
AU  - Haferkamp A
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany.
FAU - Blaheta, Roman A
AU  - Blaheta RA
AD  - Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, 
      Germany. Electronic address: Blaheta@em.uni-frankfurt.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Integrin alpha5)
RN  - 0 (Integrin beta3)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Renal Cell/*metabolism/pathology
MH  - Cell Adhesion/drug effects/genetics
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects/genetics
MH  - Drug Resistance, Neoplasm
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Integrin alpha5/genetics/*metabolism
MH  - Integrin beta3/genetics/*metabolism
MH  - Kidney Neoplasms/*metabolism/pathology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
PMC - PMC4094828
EDAT- 2014/05/28 06:00
MHDA- 2015/01/24 06:00
PMCR- 2014/05/24
CRDT- 2014/05/28 06:00
PHST- 2014/02/10 00:00 [received]
PHST- 2014/03/18 00:00 [revised]
PHST- 2014/03/19 00:00 [accepted]
PHST- 2014/05/28 06:00 [entrez]
PHST- 2014/05/28 06:00 [pubmed]
PHST- 2015/01/24 06:00 [medline]
PHST- 2014/05/24 00:00 [pmc-release]
AID - S1476-5586(14)00030-X [pii]
AID - 10.1016/j.neo.2014.03.011 [doi]
PST - ppublish
SO  - Neoplasia. 2014 Apr;16(4):291-300. doi: 10.1016/j.neo.2014.03.011.