Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro, indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations.

Detaljer

Författare
  • Janja Završnik
  • Miha Butinar
  • Mojca Trstenjak Prebanda
  • Aleksander Krajnc
  • Robert Vidmar
  • Marko Fonović
  • Anders Grubb
  • Vito Turk
  • Boris Turk
  • Olga Vasiljeva
Enheter & grupper
Externa organisationer
  • Jožef Stefan Institute
  • The Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKeBiP)
  • Skåne University Hospital
  • University of Ljubljana
  • CytomX Therapeutics, Inc.
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi

Nyckelord

Originalspråkengelska
Sidor (från-till)73793-73809
Antal sidor17
TidskriftOncotarget
Volym8
Utgåva nummer43
StatusPublished - 2017
PublikationskategoriForskning
Peer review utfördJa