RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro

Sandra Casimiro, Khalid S. Mohammad, Ricardo Pires, Joana Tato-Costa, Irina Alho, Rui Teixeira, António Carvalho, Sofia Ribeiro, Allan Lipton, Theresa A. Guise, Luis Costa

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Abstract

The osteolytic nature of bone metastasis results from a tumor-driven increased bone resorption. Bone remodeling is orchestrated by the molecular triad RANK-RANKL-OPG. This process is dysregulated in bone metastases, mostly via induction of RANKL by tumor-derived factors. These factors increase expression of RANKL, which induce osteoclast formation, function, and survival, thereby increasing bone resorption. RANK is unexpectedly expressed by cancer cells, and the activation of RANKL-RANK pathway correlates with an increased invasive phenotype. To investigate the interaction between RANK expression in human breast and prostate cancer cells and their pro-metastatic phenotype we analyzed the activation of RANKL-RANK pathway and its effects on cell migration, invasion, gene expression in vitro, and osteolysis-inducing ability in vivo. RANKL activates kinase signaling pathways, stimulates cell migration, increases cell invasion, and up-regulates MMP-1 expression. In vivo, MMP-1 knockdown resulted in smaller x-ray osteolytic lesions and osteoclastogenesis, and decreased tumor burden. Therefore, RANKL inhibition in bone metastatic disease may decrease the levels of the osteoclastogenesis inducer MMP-1, contributing to a better clinical outcome.

Original languageEnglish (US)
Article numbere63153
JournalPloS one
Volume8
Issue number5
DOIs
StatePublished - May 16 2013

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Casimiro, S., Mohammad, K. S., Pires, R., Tato-Costa, J., Alho, I., Teixeira, R., Carvalho, A., Ribeiro, S., Lipton, A., Guise, T. A., & Costa, L. (2013). RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro. PloS one, 8(5), [e63153]. https://doi.org/10.1371/journal.pone.0063153