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Protein Kinase C-Beta Inhibition Induces Apoptosis and Inhibits Cell Cycle Progression in Acquired Immunodeficiency Syndrome–Related Non-Hodgkin Lymphoma Cells
  1. Nakhle S. Saba, MD*†,
  2. Laura S. Levy, PhD†‡
  1. From the *Section of Hematology and Medical Oncology, Department of Medicine, †Tulane Cancer Center, and ‡Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA.
  1. Received February 16, 2011, and in revised form August 18, 2011.
  2. Accepted for publication September 14, 2011.
  3. Reprints: Laura S. Levy, PhD, Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Ave, SL-38, New Orleans, LA 70112. E-mail: llevy{at}tulane.edu.
  4. This work was supported by grants to LSL from the National Cancer Institute, NIH (R01 CA74731), the When Everyone Survives Foundation, and the Ladies Leukemia League, Inc, of the Gulf South Region.

Abstract

Introduction Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL) constitutes an aggressive variety of lymphomas characterized by increased extranodal involvement, relapse rate, and resistance to chemotherapy. Protein kinase C-beta (PKCβ) targeting showed promising results in preclinical and clinical studies involving a wide variety of cancers, but studies describing the role of PKCβ in AIDS-NHL are primitive if not lacking.

Methods In the present study, 3 AIDS-NHL cell lines were examined: 2F7 (AIDS–Burkitt lymphoma), BCBL-1 (AIDS–primary effusion lymphoma), and UMCL01-101 (AIDS–diffuse large B-cell lymphoma).

Results Immunoblot analysis demonstrated expression of PKCβ1 and PKCβ2 in 2F7 and UMCL01-101 cells, and PKCβ1 alone in BCBL-1 cells. The viability of 2F7 and BCBL-1 cells decreased significantly in the presence of PKCβ-selective inhibitor at half-maximal inhibitory concentration of 14 and 15 μmol/L, respectively, as measured by tetrazolium dye reduction assay. In contrast, UMCL01-101 cells were relatively resistant. As determined using flow cytometric deoxynucleotidyl transferase dUTP nick-end labeling assay with propidium iodide staining, the responsiveness of sensitive cells was associated with apoptotic induction and cell cycle inhibition. Protein kinase C-beta–selective inhibition was observed not to affect AKT phosphorylation but to induce a rapid and sustained reduction in the phosphorylation of glycogen synthase kinase-3 beta, ribosomal protein S6, and mammalian target of rapamycin in sensitive cell lines.

Conclusions The results indicate that PKCβ plays an important role in AIDS-related NHL survival and suggest that PKCβ targeting should be considered in a broader spectrum of NHL. The observations in BCBL-1 were unexpected in the absence of PKCβ2 expression and implicate PKCβ1 as a regulator in those cells.

Key Words
  • AIDS-related lymphoma
  • protein kinase C-beta
  • apoptosis
  • cell cycle inhibition
  • targeted therapy

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