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Deprecated: Implicit conversion from float 298.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Leukemia 2016 ; 30 (2): 390-8 Nephropedia Template TP
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Blocking the ZZ Domain of Sequestosome1/p62 Suppresses Myeloma Growth and Osteoclast Formation In Vitro and Induces Dramatic Bone Formation in Myeloma-Bearing Bones In Vivo #MMPMID26286116
Teramachi J; Silbermann R; Yang P; Zhao W; Mohammad KS; Guo J; Anderson JL; Zhou D; Feng R; Myint KZ; Maertz N; Beumer JH; Eiseman JL; Windle JJ; Xie XQ; Roodman GD; Kurihara N
Leukemia 2016[Feb]; 30 (2): 390-8 PMID26286116show ga
We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSC) for the formation of signaling complexes, including NF?B, p38MAPK, and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSC that are key contributors to myeloma bone disease (MMBD), and demonstrated that the ZZ-domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, that inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2?s capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of TNF?, an OBL differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.