Prokineticin-1/endocrine gland-derived vascular endothelial growth factor is a survival factor for human multiple myeloma cells.
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.
Li
Qing-Fang
QF
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
Zhu
Hai-Yan
HY
Yang
Yue-Feng
YF
Liu
Jiao
J
Xiao
Feng-Jun
FJ
Zhang
Qun-Wei
QW
Wu
Chu-Tse
CT
Wang
Hua
H
Wang
Li-Sheng
LS
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000099157:Sphingosine Kinase
D016895:Culture Media, Serum-Free; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D000099157:Sphingosine Kinase; C470837:PROKR1 protein, human