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.
Highlights
Multiple myeloma (MM) is a neoplastic proliferation of bone marrow plasma cells
In the current study we have explored the significance of Phosphatase of regenerating liver (PRL)-3 in multiple myeloma
We show that PRL-3 overexpression increased survival in the absence or with suboptimal concentrations of IL-6 in an IL-6dependent cell line
Summary
Multiple myeloma (MM) is a neoplastic proliferation of bone marrow plasma cells. The malignant cells are primarily located to the bone marrow (BM). [2] One of the challenges in myeloma therapy is this redundant stimulation of MM cells by multiple signals in the BM microenvironment. [3, 4] IL-6 enhances MM cell proliferation, survival, drug resistance and migration [5], and IL-6 levels in MM patients are correlated with advanced disease and a poor prognosis. [6, 7] Despite the fact that it is repeatedly shown that IL-6 is important in MM cell survival both in vitro and in vivo, treatment blocking IL-6 signaling has so far not proven to be an efficient approach. PRL-3 is encoded by the gene PTP4A3 and its expression in cancer cells was shown to be associated with the cells’ ability to metastasize and with a poor prognosis in multiple cancers, including breast, colon, gastric, ovarian and esophageal carcinomas. In this study we wanted to see to what extent PRL-3 is necessary and sufficient for mediating the effects of IL-6 on MM cells
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