Prokineticin-1/endocrine gland-derived vascular endothelial growth factor is a survival factor for human multiple myeloma cells

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.

Keywords:

• Multiple myeloma
• prokineticin-1 (PK1)/endocrine gland-derived vascular endothelial growth factor (VEGF)
• Mcl-1
• survival

Acknowledgements

We thank Dr. Wen-Rong Huang for providing MM samples. We thank professor Jia-Xi Wang for proofreading the manuscript.

Declaration of interest: This project was supported in part by grants from the Chinese National Basic Research and Development (973 Program) (No. 2006CB504100) and the National Natural Science Foundation of China (Nos. 30670885, 30900634 and 30930041).