Molecular targeting of the PKC-β inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression

Donata Verdelli, Lucia Nobili, Katia Todoerti, Daniela Intini, Maria Cosenza, Monica Civallero, Jessika Bertacchini, Giorgio Lambertenghi Deliliers, Stefano Sacchi, Luigia Lombardi, Antonino Neri

Research output: Contribution to journalArticlepeer-review

Abstract

The protein kinase C (PKC) pathway has been shown to play a role in the regulation of cell proliferation in several haematological malignancies, including multiple myeloma (MM). Recent data have shown that a PKC inhibitor, enzastaurin, has antiproliferative and proapoptotic activity in a large panel of human myeloma cell lines (HMCLs). In order to further characterise the effect of enzastaurin in MM, we performed gene expression profiling of enzastaurin-treated KMS-26 cell line. We identified 62 upregulated and 32 downregulated genes that are mainly involved in cellular adhesion (CXCL12, CXCR4), apoptosis (CTSB, TRAF5, BCL2L1), cell proliferation (IGF1, GADD45A, BCMA (B-cell maturation antigen), CDC20), transcription regulation (MYC, MX11, IRF4), immune and defence responses. Subsequent validation by Western blotting of selected genes in four enzastaurin-treated HMCLs was consistent with our microarray analysis. Our data indicate that enzastaurin may affect important processes involved in the proliferation and survival of malignant plasma cells as well as in their interactions with the bone marrow microenvironment and provide a preclinical rationale for the potential role of this drug in the treatment of MM.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalHematological Oncology
Volume27
Issue number1
DOIs
Publication statusPublished - 2009

Keywords

  • Cell line
  • Enzastaurin
  • Gene expression profiling
  • Molecular pathway
  • Multiple myeloma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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