Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 7, Pages 2452-2465Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000667
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [R01 CA155192, RO1 CA077474-14S1, R21 CA194868]
- Multiple Myeloma Research Foundation Senior Investigator Awards
- University of Wisconsin Carbone Cancer Center Grant [P30 CA014520]
- Trillium Fund
- NIH [T32 CA009135, R01 CA077474-14S1, T32 GM008688, F30 AG029714-02]
- University of Wisconsin-Madison
Ask authors/readers for more resources
Nuclear factor-kappa B (NF-kappa B) 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-kappa B in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-kappa B 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-kappa B pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-kappa B (I kappa B alpha), 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-kappa B activation and thereby promotes bortezomib resistance in MM cells.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available