Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells

被引:59
作者
Beristain, Alexander G. [1 ]
Narala, Swami R. [1 ]
Di Grappa, Marco A. [1 ]
Khokha, Rama [1 ]
机构
[1] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada
关键词
Autocrine; Cancer; RANKL; NF-KAPPA-B; TNF FAMILY-MEMBER; OSTEOCLAST DIFFERENTIATION; RECEPTOR ACTIVATOR; OSTEOPROTEGERIN-LIGAND; IMPROVES SURVIVAL; TUMOR BURDEN; T-CELLS; BONE; EXPRESSION;
D O I
10.1242/jcs.094029
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
RANKL (receptor activator of NF-kappa B ligand) is a crucial cytokine for regulating diverse biological systems such as innate immunity, bone homeostasis and mammary gland differentiation, operating through activation of its cognate receptor RANK. In these normal physiological processes, RANKL signals through paracrine and/or heterotypic mechanisms where its expression and function is tightly controlled. Numerous pathologies involve RANKL deregulation, such as bone loss, inflammatory diseases and cancer, and aberrant RANK expression has been reported in bone cancer. Here, we investigated the significance of RANK in tumor cells with a particular emphasis on homotypic signaling. We selected RANK-positive mouse osteosarcoma and RANK-negative preosteoblastic MC3T3-E1 cells and subjected them to loss-and gain-of-RANK function analyses. By examining a spectrum of tumorigenic properties, we demonstrate that RANK homotypic signaling has a negligible effect on cell proliferation, but promotes cell motility and anchorage-independent growth of osteosarcoma cells and preosteoblasts. By contrast, establishment of RANK signaling in non-tumorigenic mammary epithelial NMuMG cells promotes their proliferation and anchorage-independent growth, but not motility. Furthermore, RANK activation initiates multiple signaling pathways beyond its canonical target, NF-kappa B. Among these, biochemical inhibition reveals that Erk1/2 is dominant and crucial for the promotion of anchorage-independent survival and invasion of osteoblastic cells, as well as the proliferation of mammary epithelial cells. Thus, RANK signaling functionally contributes to key tumorigenic properties through a cell-autonomous homotypic mechanism. These data also identify the likely inherent differences between epithelial and mesenchymal cell responsiveness to RANK activation.
引用
收藏
页码:943 / 955
页数:13
相关论文
共 58 条
[1]   RANK-Fc inhibits malignancy via inhibiting ERK activation and evoking caspase-3-mediated anoikis in human osteosarcoma cells [J].
Akiyama, Toru ;
Choong, Peter F. M. ;
Dass, Crispin R. .
CLINICAL & EXPERIMENTAL METASTASIS, 2010, 27 (04) :207-215
[2]   A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function [J].
Anderson, DM ;
Maraskovsky, E ;
Billingsley, WL ;
Dougall, WC ;
Tometsko, ME ;
Roux, ER ;
Teepe, MC ;
DuBose, RF ;
Cosman, D ;
Galibert, L .
NATURE, 1997, 390 (6656) :175-179
[3]   RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor, metastasis genes [J].
Armstrong, Allison P. ;
Miller, Robert E. ;
Jones, Jon C. ;
Zhang, Jian ;
Keller, Evan T. ;
Dougall, William C. .
PROSTATE, 2008, 68 (01) :92-104
[4]   Integrin αv-mediated inactivation of p53 controls a MEK1-dependent melanoma cell survival pathway in three-dimensional collagen [J].
Bao, WJ ;
Strömblad, S .
JOURNAL OF CELL BIOLOGY, 2004, 167 (04) :745-756
[5]   Regulated Expression of ADAMTS-12 in Human Trophoblastic Cells: A Role for ADAMTS-12 in Epithelial Cell Invasion? [J].
Beristain, Alexander G. ;
Zhu, Hua ;
Leung, Peter C. K. .
PLOS ONE, 2011, 6 (04)
[6]   Biology of RANK, RANKL, and osteoprotegerin [J].
Boyce, Brendan F. ;
Xing, Lianping .
ARTHRITIS RESEARCH & THERAPY, 2007, 9 (Suppl 1)
[7]   osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification [J].
Bucay, N ;
Sarosi, I ;
Dunstan, CR ;
Morony, S ;
Tarpley, J ;
Capparelli, C ;
Scully, S ;
Tan, HL ;
Xu, WL ;
Lacey, DL ;
Boyle, WJ ;
Simonet, WS .
GENES & DEVELOPMENT, 1998, 12 (09) :1260-1268
[8]   Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis [J].
Canon, Jude R. ;
Roudier, Martine ;
Bryant, Rebecca ;
Morony, Sean ;
Stolina, Marina ;
Kostenuik, Paul J. ;
Dougall, William C. .
CLINICAL & EXPERIMENTAL METASTASIS, 2008, 25 (02) :119-129
[9]   IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development [J].
Cao, YX ;
Bonizzi, G ;
Seagroves, TN ;
Greten, FR ;
Johnson, R ;
Schmidt, EV ;
Karin, M .
CELL, 2001, 107 (06) :763-775
[10]   RANKL Increases Migration of Human Lung Cancer Cells Through Intercellular Adhesion Molecule-1 Up-Regulation [J].
Chen, Li-Mien ;
Kuo, Chia-Hua ;
Lai, Tung-Yuan ;
Lin, Yueh-Min ;
Su, Cheng-Chuan ;
Hsu, His-Hsien ;
Tsai, Fuu-Jen ;
Tsai, Chang-Hai ;
Huang, Chih-Yang ;
Tang, Chih-Hsin .
JOURNAL OF CELLULAR BIOCHEMISTRY, 2011, 112 (03) :933-941