Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-κB activity and increases drug resistance in multiple myeloma

J Biol Chem. 2018 Feb 16;293(7):2452-2465. doi: 10.1074/jbc.RA117.000667. Epub 2017 Dec 26.

Abstract

Nuclear factor-κB (NF-κB) is a family of transcription factors that play a key role in cell survival and proliferation in many hematological malignancies, including multiple myeloma (MM). Bortezomib, a proteasome inhibitor used in the management of MM, can inhibit both canonical and noncanonical activation of NF-κB in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-κB activity. Here, we report that hyaluronan and proteoglycan link protein 1 (HAPLN1) is produced in bone marrow stromal cells from MM patients, is detected in patients' bone marrow plasma, and can activate an atypical bortezomib-resistant NF-κB pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-κB (IκBα), despite efficient bortezomib-mediated inhibition of proteasome activity. Moreover, HAPLN1 can also confer bortezomib-resistant survival of MM cells. We propose that HAPLN1 is a novel pathogenic factor in MM that induces an atypical NF-κB activation and thereby promotes bortezomib resistance in MM cells.

Keywords: NF-kappa B (NF-KB); bortezomib; drug resistance; extracellular matrix protein; hyaluronan and proteoglycan link protein 1 (HAPLN1); matrikine; molecular biology; multiple myeloma.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Bortezomib / pharmacology*
  • Drug Resistance, Neoplasm
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteoglycans / genetics
  • Proteoglycans / metabolism*
  • Proteolysis

Substances

  • Antineoplastic Agents
  • Extracellular Matrix Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • Proteoglycans
  • link protein
  • Bortezomib
  • Proteasome Endopeptidase Complex