TY - JOUR
T1 - Protein kinase C beta in malignant pleural mesothelioma
AU - Faoroa, Leonardo
AU - Loganathan, Sivakumar
AU - Westerhoff, Maria
AU - Modi, Rahul
AU - Husain, Aliya N.
AU - Tretiakova, Maria
AU - Seiwert, Tanguy
AU - Kindler, Hedy L.
AU - Vokes, Everett E.
AU - Salgia, Ravi
PY - 2008/10
Y1 - 2008/10
N2 - Malignant pleural mesothelioma (MPM) is a disease with few therapeutic options. Protein kinase C beta (PKCβ) is involved in important cellular functions. Enzastaurin (LY317615.HCI) is a novel inhibitor of PKC in clinical development. MPM cell lines (7) and patient tumor tissues (24) were evaluated for expression of PKCβ by immunoblotting and immunohistochemistry, respectively. In-vitro cell growth assays were performed with enzastaurin with or without cisplatin. Cell migration was evaluated with the wound healing assay. Downstream signaling (survival and focal adhesion pathways) was studied by immunoblotting for related molecules in the presence of phorbol ester with or without enzastaurin. Expression for PKCβ1 was seen in all cases, with a mean integrated optical density of 152.5 (standard deviation = 95.47, n = 24), whereas PKCβ2 expression was less intense, with a mean integrated optical density of 11.45 (standard deviation = 16.27, n=21). There was a trend toward lower overall survival among patients expressing above-median PKCβl (P= 0.064), but not PKCβ2. Robust expression of PKCβl and low expression of PKCβ2 were observed in MPM cell lines. Treatment of MPM cell lines with enzastaurin revealed an IC50 of 5 μmol/l, and strong synergism was observed when combined with cisplatin. Wound healing assay revealed that treatment of H2461 cells with enzastaurin reduced migration by 59.2%. Enzastaurin treatment led to disruption of F-actin architecture. Downstream signaling showed reduced phosphorylation of AKT, FAK (focal adhesion kinase), p130Cas, S6 ribosomal protein, and paxillin. PKCβl was expressed in the majority of MPM samples. Enzastaurin has preclinical activity against MPM, and exhibited synergism with cisplatin. PKCβ inhibition in MPM might be able to reduce the invasiveness of MPM by affecting cytoskeletal function.
AB - Malignant pleural mesothelioma (MPM) is a disease with few therapeutic options. Protein kinase C beta (PKCβ) is involved in important cellular functions. Enzastaurin (LY317615.HCI) is a novel inhibitor of PKC in clinical development. MPM cell lines (7) and patient tumor tissues (24) were evaluated for expression of PKCβ by immunoblotting and immunohistochemistry, respectively. In-vitro cell growth assays were performed with enzastaurin with or without cisplatin. Cell migration was evaluated with the wound healing assay. Downstream signaling (survival and focal adhesion pathways) was studied by immunoblotting for related molecules in the presence of phorbol ester with or without enzastaurin. Expression for PKCβ1 was seen in all cases, with a mean integrated optical density of 152.5 (standard deviation = 95.47, n = 24), whereas PKCβ2 expression was less intense, with a mean integrated optical density of 11.45 (standard deviation = 16.27, n=21). There was a trend toward lower overall survival among patients expressing above-median PKCβl (P= 0.064), but not PKCβ2. Robust expression of PKCβl and low expression of PKCβ2 were observed in MPM cell lines. Treatment of MPM cell lines with enzastaurin revealed an IC50 of 5 μmol/l, and strong synergism was observed when combined with cisplatin. Wound healing assay revealed that treatment of H2461 cells with enzastaurin reduced migration by 59.2%. Enzastaurin treatment led to disruption of F-actin architecture. Downstream signaling showed reduced phosphorylation of AKT, FAK (focal adhesion kinase), p130Cas, S6 ribosomal protein, and paxillin. PKCβl was expressed in the majority of MPM samples. Enzastaurin has preclinical activity against MPM, and exhibited synergism with cisplatin. PKCβ inhibition in MPM might be able to reduce the invasiveness of MPM by affecting cytoskeletal function.
KW - Malignant pleural mesothelioma
KW - Protein kinase C
KW - Receptor tyrosine kinase
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=52649111280&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52649111280&partnerID=8YFLogxK
U2 - 10.1097/CAD.0b013e32830ce506
DO - 10.1097/CAD.0b013e32830ce506
M3 - Article
C2 - 18765998
AN - SCOPUS:52649111280
SN - 0959-4973
VL - 19
SP - 841
EP - 848
JO - Anti-cancer drugs
JF - Anti-cancer drugs
IS - 9
ER -