SYK inhibition modulates distinct PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas

Cancer Cell. 2013 Jun 10;23(6):826-38. doi: 10.1016/j.ccr.2013.05.002.

Abstract

B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large B cell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs. Herein, we characterize distinct SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity including selective repression of the pro-apoptotic HRK protein in NF-κB-low tumors. We also define SYK/PI3K-dependent cholesterol biosynthesis as a feed-forward mechanism of maintaining the integrity of BCRs in lipid rafts in DLBCLs with low or high NF-κB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary "BCR"-type DLBCLs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cholesterol / biosynthesis
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Forkhead Transcription Factors / physiology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Lymphoma, Large B-Cell, Diffuse / enzymology
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcr / metabolism*
  • Signal Transduction
  • Syk Kinase

Substances

  • Apoptosis Regulatory Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • HRK protein, human
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Cholesterol
  • Phosphatidylinositol 3-Kinase
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • BCR protein, human
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcr

Associated data

  • GEO/GSE43510