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Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma
Yoichi Imai, … , Yoshiro Maru, Toshiko Motoji
Yoichi Imai, … , Yoshiro Maru, Toshiko Motoji
Published April 21, 2016
Citation Information: JCI Insight. 2016;1(5):e85061. https://doi.org/10.1172/jci.insight.85061.
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Research Article Hematology Oncology

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

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Abstract

Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of PPP3CA, a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with high PPP3CA suggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib.

Authors

Yoichi Imai, Eri Ohta, Shu Takeda, Satoko Sunamura, Mariko Ishibashi, Hideto Tamura, Yan-hua Wang, Atsuko Deguchi, Junji Tanaka, Yoshiro Maru, Toshiko Motoji

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Figure 1

High expression of PPP3CA (protein phosphatase 3, catalytic subunit, an isozyme) mRNA in advanced MM (multiple myeloma) mRNA in advanced MM patients.

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High expression of PPP3CA (protein phosphatase 3, catalytic subunit, an ...
(A) PPP3CA mRNA expression in non-MM (n = 12) and MM cell lines (n = 6) is displayed. Non-MM cell lines are as follows. Acute myeloid leukemia–derived: HEL, HL60, KG-1, THP-1, and U937; B cell acute lymphoblastic leukemia: BALL-1 and NALM6; T cell acute lymphoblastic leukemia (T-ALL): Jurkat and Molt-4; chronic myelogenous leukemia: K562; and B cell lymphoma: Daudi and Raji. MM cell lines are as follows: U266, KMS-11, KMS-12PE, KMS-18, KMS-26, and RPMI8226. Horizontal line, median. Difference between 2 groups was analyzed using 1-tailed t test. *, significant. Two biologically independent experiments were performed. (B) PPP3CA mRNA expression in MM patients with stage I (n = 9), II (n = 14), or III (n = 19) is displayed. D-S, Duri-Salmon classification. Horizontal line, median. The differences between 3 groups of samples was analyzed by ANOVA by the 1-way layout. When the statistic model proved significant, the differences between combinations of the 2 groups were analyzed using a Tukey-Kramer test for multiple comparisons.*, significant. (C) PPP3CA mRNA expression in MM patients with normal (n = 29) or abnormal (n = 17) serum LDH is displayed. Horizontal line, median. Difference between 2 groups was analyzed using 1-tailed t test. *, significant. (D) mRNA expression of PPP3CA and α4 integrins in samples from MM patients reported in the study of Agnelli (20). Correlation coefficient between PPP3CA and α4 integrins expression is displayed.

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