Parathyroid hormone receptor mediates the anti-myeloma effect of proteasome inhibitors

Abstract

Clinically significant serum parathyroid hormone (PTH) variations have been reported in multiple myeloma (MM) patients treated with proteasome inhibitors. To elucidate the association between serum PTH variations and proteasome inhibition in MM, the effect of PTH and PTHR1 ligands on the proteasome inhibitors bortezomib and carfilzomib in vitro and in vivo was determined. The MM cell lines ARP1, OC1 and 5TGM1 expressed mRNA and protein encoding PTH receptor 1 (PTHR1). Treatment of 5TGM1 cells with either PTH(1–34), bortezomib or carfilzomib alone dose-dependently inhibited 5TGM1 cell proliferation. However, treatment with the potent PTHR1 antagonist [TYR34]PTH(7–34) (PTH(7–34)) had no significant effect on myeloma cell proliferation and cell viability. In contrast, when used in combination with bortezomib or carfilzomib, PTH(7–34) treatment significantly reduced the bortezomib or carfilzomib-associated decrease in cell proliferation. Treatment of the C57BL/KaLwRij mouse myeloma model with either bortezomib or carfilzomib provided a significantly prolonged survival benefit compared to controls (p=0.04; p=0.01 respectfully). This potent anti-myeloma effect was completely abrogated by concomitant treatment with PTH(7–34). These results suggest an important role of the PTHR1 in the anti-myeloma effect of proteosome inhibition.

The Proteasome Inhibitor Bortezomib Maintains Osteocyte Viability in Multiple Myeloma Patients by Reducing Both Apoptosis and Autophagy: A New Function for Proteasome Inhibitors

“…Our data showed that the positive effect of BOR on DEX‐induced osteocyte death was enhanced when combined with a PTH(1‐34) short‐term treatment compared with treatment with BOR and PTH(1‐34) alone. PTH receptor signaling has been recently reported to mediate the anti‐myeloma effect of PIs, including BOR …”

“…PTH receptor signaling has been recently reported to mediate the anti-myeloma effect of PIs, including BOR. (45) The mechanisms involved in MM-induced osteocyte death and the protective effect of PIs on osteocyte survival were further investigated. First, we found that autophagic death rather than apoptosis was involved in our experimental model, in either human preosteocytes or murine osteocytes, as shown by both the increased expression of the autophagy marker LC3II by Western blot and confocal microscopy and the lack of effect on caspase-3 activation and APAF-1 expression.…”

The effects of proteasome inhibitors on bone remodeling in multiple myeloma

“…This observation suggested that the anti-MM activity of bortezomib may depend on the presence of PTH and/or its receptors. Supporting this hypothesis, the anti-MM activity of bortezomib was shown to be mediated by PTHR1; concomitant treatment with a PTHR1 antagonist was found to abrogate the antitumor effect of bortezomib in a mouse model of MM [72]. Preliminary evidence also indicates that a higher expression level of PTHR1 or PTHR2 in bone marrow is associated with longer overall survival in patients with newly diagnosed MM who were enrolled in Total Therapy 3 (where bortezomib is part of the treatment regimen) [73,74].…”

“…As with bortezomib, PTHR1 has been shown to mediate the anti-MM effect of carfilzomib treatment in a mouse model of MM [72]. Preclinically, carfilzomib has been shown to block PTH-induced osteoclastogenesis via inhibition of the proteasomal degradation of HDAC4 in osteoblasts and disruption of RANKL-induced NF-κB activation in osteoclasts [84].…”

Surgical thyroparathyroidectomy prevents progression of 5TGM1 murine multiple myeloma in vivo

“…We have previously demonstrated a close interaction between the parathyroid hormone (PTH)/PTH receptor 1 (PTHR1) system and myeloma progression in vitro and in vivo [10] . Specifically, a close parallelism between rapid and transient spikes in PTH levels following proteasome inhibitor therapy and the control of myeloma progression [11] .…”