TY - JOUR
T1 - Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-B activity and increases drug resistance in multiple myeloma
AU - Huynh, Mailee
AU - Pak, Chorom
AU - Markovina, Stephanie
AU - Callander, Natalie S.
AU - Chng, Kenneth S.
AU - Wuerzberger-Davis, Shelly M.
AU - Bakshi, Debayan D.
AU - Kink, John A.
AU - Hematti, Peiman
AU - Hope, Chelsea
AU - Asimakopoulos, Fotis
AU - Rui, Lixin
AU - Miyamoto, Shigeki
N1 - Funding Information:
This study was supported by National Institutes of Health (NIH) Grants R01 CA155192, RO1 CA077474-14S1, and R21 CA194868 and Multiple Myeloma Research Foundation Senior Investigator Awards (to S. Miyamoto); University of Wisconsin Carbone Cancer Center Grant P30 CA014520 and the Trillium Fund (to S. Miyamoto, N. S. C., F. A., and P. H.); NIH Grant T32 CA009135 (to M. H. and C. P); NIH Grant R01 CA077474-14S1 (to M. H.); the SciMed Graduate Research Scholars Fellowship at the University of Wisconsin-Madison (to M. H.); NIH Grant T32 GM008688 (C. P.); and NIH Grant F30 AG029714-02 (to S. Markovina). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This study was supported by National Institutes of Health (NIH) Grants R01 CA155192, RO1 CA077474-14S1, and R21 CA194868 and Multiple Myeloma Research Foundation Senior Investigator Awards (to S. Miy-amoto); University of Wisconsin Carbone Cancer Center Grant P30 CA014520 and the Trillium Fund (to S. Miyamoto, N. S. C., F. A., and P. H.); NIH Grant T32 CA009135 (to M. H. and C. P); NIH Grant R01 CA077474-14S1 (to M. H.); the SciMed Graduate Research Scholars Fellowship at the Uni-versity of Wisconsin-Madison (to M. H.); NIH Grant T32 GM008688 (C. P.); and NIH Grant F30 AG029714-02 (to S. Markovina). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2018/2/16
Y1 - 2018/2/16
N2 - Nuclear factor-B (NF-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-B in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-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-B pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-B (IB), 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-B activation and thereby promotes bortezomib resistance in MM cells.
AB - Nuclear factor-B (NF-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-B in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-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-B pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-B (IB), 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-B activation and thereby promotes bortezomib resistance in MM cells.
UR - http://www.scopus.com/inward/record.url?scp=85042184901&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA117.000667
DO - 10.1074/jbc.RA117.000667
M3 - Article
C2 - 29279332
AN - SCOPUS:85042184901
SN - 0021-9258
VL - 293
SP - 2452
EP - 2465
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
ER -