Abstract
Prokineticin-1 (PK1) has been identified as a mitogen-specific protein for the endothelium of steroidogenic glands. Here we report a novel function of PK1 in the regulation of multiple myeloma (MM) cells. PK1 activates multiple signals including mitogen-activated protein kinase (MAPK), PI3K-AKT, and Jak-STAT3, sphingosine kinase-1 (SPK1) in MM cells. Treatment of MM cells with PK1 causes a time- and dose-dependent phosphorylation of MAPK, AKT and STAT3 and upregulation of SPK1 expression and cellular activity. We also show that PK1 upregulates Mcl-1 expression in a time- and dose-dependent manner in human MM cell lines and in the cells of patients with MM. Pertussis toxin, a pan-PK1 receptor inhibitor, can block PK1-induced upregulation of Mcl-1, indicating it relates to a G-protein-coupled receptor. We also show that PK1 protects MM cells against apoptosis induced by starvation for fetal calf serum (FBS), or for FBS and IL-6. Taken together, PK1 activates multiple signaling pathways and, upregulates Mcl-1 expression, leading to proliferation and survival of MM cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Culture Media, Serum-Free / pharmacology
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Gene Expression
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Humans
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Immunohistochemistry
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Interleukin-6 / pharmacology
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Mitogen-Activated Protein Kinases / metabolism
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphorylation / drug effects
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Recombinant Proteins / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / metabolism
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / genetics
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Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / metabolism
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Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / pharmacology*
Substances
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Culture Media, Serum-Free
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Interleukin-6
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Myeloid Cell Leukemia Sequence 1 Protein
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PROKR1 protein, human
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Proto-Oncogene Proteins c-bcl-2
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Receptors, G-Protein-Coupled
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Recombinant Proteins
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STAT3 Transcription Factor
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Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases