MEK inhibitor diminishes nasopharyngeal carcinoma (NPC) cell growth and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions

Tumour Biol. 2015 Nov;36(11):8811-8. doi: 10.1007/s13277-015-3595-8. Epub 2015 Jun 10.

Abstract

Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. NPC frequently metastasizes to the bone in advanced patients resulting in high mortality. The molecular mechanisms for NPC development and cancer-induced bone lesions are unclear. In this study, we firstly determined chemokine receptor CCR2 and CXCR6 expressions in clinical specimens and CNE2, SUNE1, CNE1, and HK1 cell lines. Then, we measured chemokine CCL2 and CXCL16 production in these NPC cell lines by ELISA. Expression levels of these chemokines and their receptors were observed to positively correlate with tumor aggressiveness. Furthermore, U0126 (MEK inhibitor) was used to treat these NPC cell lines. CCL2 and CXCL16 expression levels and cell proliferation were significantly inhibited by U0126 in a dose- and time-dependent manner. Finally, we collected conditioned medium (CM) from NPC cell cultures in the presence of U0126 treatment. When mouse bone marrow non-adherent cells were treated with the CM, the numbers of multinucleated osteoclast formation were dramatically diminished. These results indicate that MEK inhibitor diminishes NPC cell proliferation and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions. This study provides novel therapeutic targets such as CCL2/CCR2 and CXCL16/CXCR6 for advanced NPC patients.

Keywords: CCL2/CCR2; CXCL16/CXCR6; Nasopharyngeal carcinoma; Osteoclastogenesis; U0126.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / drug effects
  • Butadienes / administration & dosage
  • Carcinoma
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemokine CCL2 / biosynthesis*
  • Chemokine CCL2 / genetics
  • Chemokine CXCL16
  • Chemokines, CXC / biosynthesis*
  • Chemokines, CXC / genetics
  • Culture Media, Conditioned / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics*
  • Mice
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / drug therapy
  • Nasopharyngeal Neoplasms / genetics*
  • Nasopharyngeal Neoplasms / pathology
  • Nitriles / administration & dosage
  • Osteoclasts / drug effects
  • Osteoclasts / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Receptors, Scavenger / biosynthesis*
  • Receptors, Scavenger / genetics

Substances

  • Butadienes
  • CCL2 protein, human
  • CXCL16 protein, human
  • Chemokine CCL2
  • Chemokine CXCL16
  • Chemokines, CXC
  • Culture Media, Conditioned
  • Nitriles
  • Protein Kinase Inhibitors
  • Receptors, Scavenger
  • U 0126
  • MAP Kinase Kinase Kinases