PMID- 16166321
OWN - NLM
STAT- MEDLINE
DCOM- 20051125
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 18
DP  - 2005 Sep 15
TI  - Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin 
      pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung 
      cancer cellular survival and resistance to imatinib mesylate or chemotherapy.
PG  - 8423-32
AB  - The fact that small cell lung cancer (SCLC) is commonly incurable despite being 
      initially responsive to chemotherapy, combined with disappointing results from a 
      recent SCLC clinical trial with imatinib, has intensified efforts to identify 
      mechanisms of SCLC resistance. Adhesion to extracellular matrix (ECM) is one 
      mechanism that can increase therapeutic resistance in SCLC cells. To address 
      whether adhesion to ECM increases resistance through modulation of signaling 
      pathways, a series of SCLC cell lines were plated on various ECM components, and 
      activation of two signaling pathways that promote cellular survival, the 
      phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) 
      pathway and the mitogen-activated protein kinase kinase/extracellular 
      signal-regulated kinase (MEK/ERK) pathway, was assessed. Although differential 
      activation was observed, adhesion to laminin increased Akt activation, increased 
      cellular survival after serum starvation, and caused the cells to assume a 
      flattened, epithelial morphology. Inhibitors of the PI3K/Akt/mTOR pathway 
      (LY294002, rapamycin) but not the MEK/ERK pathway (U0126) abrogated 
      laminin-mediated survival. SCLC cells plated on laminin were not only resistant 
      to serum starvation-induced apoptosis but were also resistant to apoptosis caused 
      by imatinib. Combining imatinib with LY294002 or rapamycin but not U0126 caused 
      greater than additive increases in apoptosis compared with apoptosis caused by 
      the inhibitor or imatinib alone. Similar results were observed when adenoviruses 
      expressing mutant Akt were combined with imatinib, or when LY294002 was combined 
      with cisplatin or etoposide. These studies identify laminin-mediated activation 
      of the PI3K/Akt/mTOR pathway as a mechanism of cellular survival and therapeutic 
      resistance in SCLC cells and suggest that inhibition of the PI3K/Akt/mTOR pathway 
      is one strategy to overcome SCLC resistance mediated by ECM.
FAU - Tsurutani, Junji
AU  - Tsurutani J
AD  - Cancer Therapeutics Branch, Center for Cancer Research, National Cancer 
      Institute, Bethesda, Maryland 20889, USA.
FAU - West, Kip A
AU  - West KA
FAU - Sayyah, Jacqueline
AU  - Sayyah J
FAU - Gills, Joell J
AU  - Gills JJ
FAU - Dennis, Phillip A
AU  - Dennis PA
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Chromones)
RN  - 0 (Laminin)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.- (Protein Kinases)
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  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Benzamides
MH  - Carcinoma, Small Cell/*enzymology/pathology
MH  - Cell Adhesion/physiology
MH  - Cell Survival/drug effects/physiology
MH  - Chromones/pharmacology
MH  - Drug Resistance, Neoplasm
MH  - Enzyme Activation
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism
MH  - Humans
MH  - Imatinib Mesylate
MH  - Laminin/pharmacology
MH  - Lung Neoplasms/*enzymology/pathology
MH  - MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Piperazines/*pharmacology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/metabolism
MH  - Pyrimidines/*pharmacology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2005/09/17 09:00
MHDA- 2005/12/13 09:00
CRDT- 2005/09/17 09:00
PHST- 2005/09/17 09:00 [pubmed]
PHST- 2005/12/13 09:00 [medline]
PHST- 2005/09/17 09:00 [entrez]
AID - 65/18/8423 [pii]
AID - 10.1158/0008-5472.CAN-05-0058 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Sep 15;65(18):8423-32. doi: 10.1158/0008-5472.CAN-05-0058.