Mimetics of suppressor of cytokine signaling 3: Novel potential therapeutics in triple breast cancer

Int J Cancer. 2018 Nov 1;143(9):2177-2186. doi: 10.1002/ijc.31594. Epub 2018 Aug 11.

Abstract

Suppressor of cytokine signaling (SOCS) family of proteins plays critical role in the regulation of immune responses controlling JAK/STAT mediated inflammatory cytokines. Among the members, SOCS1 and SOCS3 contain a kinase inhibitory region (KIR) and SOCS3 binds to JAK/STAT/gp130 complex by inhibiting the downstream signaling and suppressing inflammatory cytokines. Loss or reduced levels of SOCS3 have been linked to cancer-associated inflammation and suppressive immunity leading to enhanced tumor growth and metastasis. In line with these reports, we previously demonstrated that proteolytic degradation of SOCS3 in triple negative breast cancer (TNBC) subtype drives the expression of inflammatory cytokines. Therefore, we postulated that SOCS3 mimetics might suppress the inflammatory cytokine production in TNBC subtype and inhibit tumor growth and metastasis. Here we designed and characterized five linear peptides derived from the N-terminal region of SOCS3 encompassing regions that interface with the JAK2/gp130 complex using the Circular Dichroism and Surface Plasmon Resonance spectroscopies. The KIRESS peptide resulted the sequence containing the most part of the hot-spots required for binding to JAK2 and was further investigated in vivo in mouse xenografts of MDA-MB-231-luci tumors as models of human TNBC subtype. Expectedly, this peptide showed a significant inhibition of primary tumor growth and pulmonary metastasis. Our studies suggest that SOCS3 peptidomimetics may possess a therapeutic potential in aggressive cancers, such as TNBC subtype, with activated inflammatory cytokines.

Keywords: cytokine signaling; mimetic peptides; triple breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / metabolism
  • Biomimetics*
  • Cell Proliferation
  • Cytokines / metabolism
  • Female
  • Humans
  • Janus Kinase 2 / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Protein Conformation
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein / chemistry
  • Suppressor of Cytokine Signaling 3 Protein / metabolism*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Cytokines
  • Peptide Fragments
  • SOCS3 protein, human
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • JAK2 protein, human
  • Janus Kinase 2