Protein kinase C beta in malignant pleural mesothelioma

Leonardo Faoroa, Sivakumar Loganathan, Maria Westerhoff, Rahul Modi, Aliya N. Husain, Maria Tretiakova, Tanguy Lim Seiwert, Hedy L. Kindler, Everett E. Vokes, Ravi Salgia

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)841-848
Number of pages8
JournalAnti-Cancer Drugs
Volume19
Issue number9
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Pleural Neoplasms
Protein Kinase C beta
Indoles
Mesothelioma
Receptor Protein-Tyrosine Kinases
Phorbol Esters
Protein Kinase Inhibitors
Tumor Cell Line
Protein Kinase C
Cisplatin
Inhibitory Concentration 50
Cell Movement
Phosphorylation
Cell Proliferation
Therapeutics
Immunoblotting
Cell Line
Wound Healing
Ribosomal Protein S6
Paxillin

Keywords

  • Malignant pleural mesothelioma
  • Protein kinase C
  • Receptor tyrosine kinase
  • Therapy

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

Cite this

Faoroa, L., Loganathan, S., Westerhoff, M., Modi, R., Husain, A. N., Tretiakova, M., ... Salgia, R. (2008). Protein kinase C beta in malignant pleural mesothelioma. Anti-Cancer Drugs, 19(9), 841-848. https://doi.org/10.1097/CAD.0b013e32830ce506

Protein kinase C beta in malignant pleural mesothelioma. / Faoroa, Leonardo; Loganathan, Sivakumar; Westerhoff, Maria; Modi, Rahul; Husain, Aliya N.; Tretiakova, Maria; Lim Seiwert, Tanguy; Kindler, Hedy L.; Vokes, Everett E.; Salgia, Ravi.

In: Anti-Cancer Drugs, Vol. 19, No. 9, 01.10.2008, p. 841-848.

Research output: Contribution to journalArticle

Faoroa, L, Loganathan, S, Westerhoff, M, Modi, R, Husain, AN, Tretiakova, M, Lim Seiwert, T, Kindler, HL, Vokes, EE & Salgia, R 2008, 'Protein kinase C beta in malignant pleural mesothelioma', Anti-Cancer Drugs, vol. 19, no. 9, pp. 841-848. https://doi.org/10.1097/CAD.0b013e32830ce506
Faoroa L, Loganathan S, Westerhoff M, Modi R, Husain AN, Tretiakova M et al. Protein kinase C beta in malignant pleural mesothelioma. Anti-Cancer Drugs. 2008 Oct 1;19(9):841-848. https://doi.org/10.1097/CAD.0b013e32830ce506
Faoroa, Leonardo ; Loganathan, Sivakumar ; Westerhoff, Maria ; Modi, Rahul ; Husain, Aliya N. ; Tretiakova, Maria ; Lim Seiwert, Tanguy ; Kindler, Hedy L. ; Vokes, Everett E. ; Salgia, Ravi. / Protein kinase C beta in malignant pleural mesothelioma. In: Anti-Cancer Drugs. 2008 ; Vol. 19, No. 9. pp. 841-848.
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