J Breast Cancer.  2019 Sep;22(3):362-374. 10.4048/jbc.2019.22.e34.

Anticancer Activity of Tubulosine through Suppression of Interleukin-6-Induced Janus Kinase 2/Signal Transducer and Activation of Transcription 3 Signaling

Affiliations
  • 1Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. sangkyu@snu.ac.kr
  • 2Biomedical Science Project (BK21 PLUS), Seoul National University College of Medicine, Seoul, Korea.
  • 3Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
  • 4Department of Oriental Rehabilitation Medicine, College of Oriental Medicine, Daejeon University, Daejeon, Korea.
  • 5Division of Basic Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
  • 6Department of Applied Chemistry, Daejeon University, Daejeon, Korea.
  • 7Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul, Korea.

Abstract

PURPOSE
The chemical structure of tubulosine has been known since the mid-1960s. However, little is known about its biological and pharmacological functions. The aim of this study was to investigate the novel functions of tubulosine in cancer treatment, specifically in breast cancer.
METHODS
An Unpaired (Upd)-induced Drosophila cell line and interleukin (IL)-6-stimulated human breast cancer cell lines were used to investigate the biological and pharmacological activities of tubulosine in vitro. To investigate the activities of tubulosine, we performed molecular and cellular experiments such as Western blot and reverse transcription polymerase chain reaction analyses, immunoprecipitation and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunofluorescence staining using breast cancer cell lines.
RESULTS
Tubulosine exhibited anticancer activity in IL-6-stimulated human breast cancer cells. Moreover, tubulosine reduced the tyrosine phosphorylation level and transcriptional activity of signal transducer and activator of transcription (STAT) protein at 92E in Upd-induced Drosophila cells. Additionally, tubulosine suppressed IL-6-induced Janus kinase 2 (JAK2)/STAT3 signaling, resulting in decreased viability and induction of apoptotic cell death in breast cancer cells. Interestingly, inhibition of IL-6-induced JAK2/STAT3 signaling by tubulosine was associated with the blocking of IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) binding.
CONCLUSION
Tubulosine exhibits anticancer activity through functional inhibition of IL-6-induced JAK2/STAT3 signaling by targeting IL-6Rα/gp130 binding in breast cancer cells. These findings suggest that tubulosine may hold promise for the treatment of inflammation-associated cancers, including breast cancer.

Keyword

Breast neoplasms; IL-6; Janus Kinase 2; STAT3 Transcription Factor; Tubulosine

MeSH Terms

Blotting, Western
Breast Neoplasms
Cell Death
Cell Line
DNA Nucleotidylexotransferase
Drosophila
Fluorescent Antibody Technique
Glycoproteins
Humans
Immunoprecipitation
In Vitro Techniques
Interleukin-6
Interleukins
Janus Kinase 2
Phosphorylation
Phosphotransferases*
Polymerase Chain Reaction
Receptors, Interleukin-6
Reverse Transcription
STAT3 Transcription Factor
Transducers*
Tyrosine
DNA Nucleotidylexotransferase
Glycoproteins
Interleukin-6
Interleukins
Janus Kinase 2
Phosphotransferases
Receptors, Interleukin-6
STAT3 Transcription Factor
Tyrosine
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