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

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.

A three‐gene DNA methylation biomarker accurately classifies early stage prostate cancer

“…HAPLN3 belongs to the hyaluronan and proteoglycan binding link protein gene family, which functions to maintain the extracellular matrix to support tissue architecture . Although this family of proteins has been previously found to be involved in drug resistance in multiple myeloma, the functional role of HAPLN3 in prostate epithelia is poorly understood, as are the consequences of DNA methylation at this locus . Their consistent hypermethylation levels in prostate cancer point to the importance of the further investigation to elucidate the roles for GAS6 and HAPLN3 in prostate biology and disease.…”

“…belongs to the hyaluronan and proteoglycan binding link protein gene family, which functions to maintain the extracellular matrix to support tissue architecture. 88 Although this family of proteins has been previously found to be involved in drug resistance in multiple myeloma, 89 (Table S4), whereas the threegene classifier would cut the misclassification rate by over two-fold, misclassifying only 124 men (67 FP and 57 FN) ( Table 3).…”

JaponiconeA Induces Apoptosis of Bortezomib-Sensitive and –Resistant Myeloma Cells In Vitro and In Vivo through Targeting IKKβ

“…It is urgent to explore novel agents to overcome the drug resistance. NF-κB signaling pathway was found to play a signi cant role in the promotion of MM and bortezomib resistance (11,25). And inhibition of NF-κB pathway has been reported to be able to overcome bortezomib resistance.…”

Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor

“…Despite no evidence is available about a role of this transcription factor in the regulation of PVR gene expression in cancer cells, a search for sequence homology revealed the presence of putative NF-kB binding sites (-254- To identify possible molecular mediators involved in the upregulation of PVR by BMSCs, we focused our attention on NF-kB family transcription factors. These proteins are constitutively active in MM cells but a number of studies demonstrated increased NF-kB activity in MM cells in response to soluble factors produced by BMSCs [9,[39][40][41]. Despite no evidence is available about a role of this transcription factor in the regulation of PVR gene expression in cancer cells, a search for sequence homology revealed the presence of putative NF-kB binding sites (-254-GGGGAGGGCCAG-243; and -162-GTGGGTATTCCC-150) in the region of PVR(B) promoter spanning −343 bp from the transcription start site.…”