PMID- 22307455
OWN - NLM
STAT- MEDLINE
DCOM- 20121108
LR  - 20211203
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 131
IP  - 9
DP  - 2012 Nov 1
TI  - Remarkable inhibition of mTOR signaling by the combination of rapamycin and 
      1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells.
PG  - 2134-42
LID - 10.1002/ijc.27468 [doi]
AB  - Preclinical studies and clinical analyses have implicated the mammalian target of 
      rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR 
      as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs 
      to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that 
      the synthetic organoselenium compound, p-XSC, effectively inhibits viability and 
      critical signaling molecules (e.g., androgen receptor, Akt) in androgen 
      responsive (AR) and androgen independent (AI) human prostate cancer cells. On the 
      basis of its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an 
      upstream regulator of the kinase. We further hypothesized that combining p-XSC 
      with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy 
      for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone 
      or in combination, on viability and mTOR signaling were examined in AR LNCaP 
      prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream 
      targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of 
      mTORC1- and mTORC2-specific proteins with mTOR was probed through 
      immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 
      downstream targets, Akt and PCKalpha, and decreased the levels of rictor, an 
      mTORC2-specific protein, coimmunoprecipitated with mTOR in C4-2 cells. The 
      combination of p-XSC and rapamycin more effectively inhibited viability and mTOR 
      signaling in C4-2, LNCaP and DU145 cells than either agent individually.
CI  - Copyright (c) 2012 UICC.
FAU - Facompre, Nicole D
AU  - Facompre ND
AD  - Department of Biochemistry and Molecular Biology, Pennsylvania State University 
      College of Medicine, Penn State Hershey Cancer Institute, Hershey, PA PA 17033, 
      USA.
FAU - Sinha, Indu
AU  - Sinha I
FAU - El-Bayoumy, Karam
AU  - El-Bayoumy K
FAU - Pinto, John T
AU  - Pinto JT
FAU - Sinha, Raghu
AU  - Sinha R
LA  - eng
GR  - CA111842/CA/NCI NIH HHS/United States
GR  - R01 CA111842/CA/NCI NIH HHS/United States
GR  - R01 CA111842-01A2/CA/NCI NIH HHS/United States
GR  - R01 CA127729/CA/NCI NIH HHS/United States
GR  - R01 CA127729-01A2/CA/NCI NIH HHS/United States
GR  - CA127729/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120320
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Carrier Proteins)
RN  - 0 (Organoselenium Compounds)
RN  - 0 (RICTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 85539-83-9 (1,4-phenylenebis(methylene)selenocyanate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Carrier Proteins/analysis
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Male
MH  - Organoselenium Compounds/*pharmacology
MH  - Phosphorylation/drug effects
MH  - Prostatic Neoplasms/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3398165
MID - NIHMS361363
EDAT- 2012/02/07 06:00
MHDA- 2012/11/09 06:00
PMCR- 2013/11/01
CRDT- 2012/02/07 06:00
PHST- 2011/08/17 00:00 [received]
PHST- 2012/01/16 00:00 [accepted]
PHST- 2012/02/07 06:00 [entrez]
PHST- 2012/02/07 06:00 [pubmed]
PHST- 2012/11/09 06:00 [medline]
PHST- 2013/11/01 00:00 [pmc-release]
AID - 10.1002/ijc.27468 [doi]
PST - ppublish
SO  - Int J Cancer. 2012 Nov 1;131(9):2134-42. doi: 10.1002/ijc.27468. Epub 2012 Mar 
      20.