Oncotarget

Research Papers:

The phosphatase of regenerating liver-3 (PRL-3) is important for IL-6-mediated survival of myeloma cells

Tobias S. Slørdahl _, Pegah Abdollahi, Esten N. Vandsemb, Christoph Rampa, Kristine Misund, Katarzyna A. Baranowska, Marita Westhrin, Anders Waage, Torstein B. Rø and Magne Børset

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Oncotarget. 2016; 7:27295-27306. https://doi.org/10.18632/oncotarget.8422

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Abstract

Tobias S. Slørdahl1,2,3, Pegah Abdollahi1,2, Esten N. Vandsemb1,2, Christoph Rampa1,2, Kristine Misund1,2, Katarzyna A. Baranowska1,2,4, Marita Westhrin1,2, Anders Waage1,2,4, Torstein B. Rø1,2,5, Magne Børset1,2,6

1K. G. Jebsen Center for Myeloma Research, Trondheim, Norway

2Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

3Clinic of Medicine, St Olavs University Hospital, Trondheim, Norway

4Department of Hematology, St Olavs University Hospital, Trondheim, Norway

5Department of Pediatrics, St Olavs University Hospital, Trondheim, Norway

6Department of Immunology and Transfusion Medicine, St Olavs University Hospital, Trondheim, Norway

Correspondence to:

Tobias S. Slørdahl, e-mail: [email protected]

Keywords: multiple myeloma, PRL-3, PTP4A3, IL-6, STAT-3

Received: October 06, 2015     Accepted: March 14, 2016     Published: March 27, 2016

ABSTRACT

Multiple myeloma (MM) is a neoplastic proliferation of bone marrow plasma cells. PRL-3 is a phosphatase induced by interleukin (IL)-6 and other growth factors in MM cells and promotes MM-cell migration. PRL-3 has also been identified as a marker gene for a subgroup of patients with MM. In this study we found that forced expression of PRL-3 in the MM cell line INA-6 led to increased survival of cells that were depleted of IL-6. It also caused redistribution of cells in cell cycle, with an increased number of cells in G2M-phase. Furthermore, forced PRL-3 expression significantly increased phosphorylation of Signal transducer and activator of transcription (STAT) 3 both in the presence and the absence of IL-6. Knockdown of PRL-3 with shRNA reduced survival in MM cell line INA-6. A pharmacological inhibitor of PRL-3 reduced survival in the MM cell lines INA-6, ANBL-6, IH-1, OH-2 and RPMI8226. The inhibitor also reduced survival in 9 of 9 consecutive samples of purified primary myeloma cells. Treatment with the inhibitor down-regulated the anti-apoptotic protein Mcl-1 and led to activation of the intrinsic apoptotic pathway. Inhibition of PRL-3 also reduced IL-6-induced phosphorylation of STAT3. In conclusion, our study shows that PRL-3 is an important mediator of growth factor signaling in MM cells and hence possibly a good target for treatment of MM.


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