Tetrahydrobiopterin induces proteasome inhibitor resistance and tumor progression in multiple myeloma.

Multiple myeloma (MM) still remains an incurable disease due to widespread drug resistance and high frequency of relapse. In this study, we found that tetrahydrobiopterin (BH4) promotes MM cell proliferation and tumor growth in vivo. BH4 also increases MM bortezomib (Bor) resistance in vitro and in vivo. We show that BH4 increases the expressions of USP7 and USP46 in MM cells, which are responsible for MM Bor resistance primed by BH4. BH4 promotes the degradation of P53 and the activation of NF-κB signaling through the up-regulation of USP7 and USP46. Furthermore, the inhibition of USPs increases the therapeutic effects of Bor in MM tumor bearing mice. Our results demonstrate the important role of BH4 in MM Bor resistance and tumor progression in vivo. These findings could potentially have clinical implications.