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Minocycline suppresses interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: in vitro and in vivo studies.

Abstract
Interleukin (IL)-6 has been shown to be a major contributing factor in growth and progression of ovarian cancer. The cytokine exerts pro-tumorigenic activity through activation of several signaling pathways in particular signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK)1/2. Hence, targeting IL-6 is becoming increasingly attractive as a treatment option in ovarian cancer. Here, we investigated the effects of minocycline on IL-6 and its signaling pathways in ovarian cancer. In vitro, minocycline was found to significantly suppress both constitutive and IL-1β or 4-hydroxyestradiol (4-OH-E2)-stimulated IL-6 expression in human ovarian cancer cells; OVCAR-3, SKOV-3 and CAOV-3. Moreover, minocycline down-regulated two major components of IL-6 receptor system (IL-6Rα and gp130) and blocked the activation of STAT3 and ERK1/2 pathways leading to suppression of the downstream product MCL-1. In female nude mice bearing intraperitoneal OVCAR-3 tumors, acute administration (4 and 24 h) of minocycline (30 mg/kg) led to suppression of IL-6. Even single dose of minocycline was effective at significantly lowering plasma and tumor IL-6 levels. In line with this, tumoral expression of p-STAT3, p-ERK1/2 and MCL-1 were decreased in minocycline-treated mice. Evaluation of the functional implication of minocycline on metastatic activity revealed the capacity of minocycline to inhibit cellular migration, invasion and adhesion associated with down-regulation of matrix metalloproteinases (MMP)-2 and 9. Thus, the data suggest a potential role for minocycline in suppressing IL-6 expression and activity. These effects may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer.
AuthorsParvin Ataie-Kachoie, David L Morris, Mohammad H Pourgholami
JournalPloS one (PLoS One) Vol. 8 Issue 4 Pg. e60817 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23593315 (Publication Type: Journal Article)
Chemical References
  • Estrogens, Catechol
  • Interleukin-1beta
  • Interleukin-6
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor
  • 4-hydroxyestradiol
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Minocycline
Topics
  • Active Transport, Cell Nucleus (drug effects)
  • Animals
  • Cell Adhesion (drug effects)
  • Cell Line, Tumor
  • Cell Movement (drug effects)
  • Cell Nucleus (drug effects, metabolism)
  • Estrogens, Catechol (pharmacology)
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Interleukin-1beta (pharmacology)
  • Interleukin-6 (metabolism)
  • Matrix Metalloproteinase 2 (metabolism)
  • Matrix Metalloproteinase 9 (metabolism)
  • Mice
  • Minocycline (pharmacology)
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Invasiveness
  • Ovarian Neoplasms (pathology)
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Receptors, Interleukin-6 (metabolism)
  • STAT3 Transcription Factor (metabolism)
  • Signal Transduction (drug effects)

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