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Par6 is an essential mediator of apoptotic response to transforming growth factor beta in NMuMG immortalized mammary

Geordon Avery-Cooper, Meghan Doerr, Richard Wd Gilbert

  • 1Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Room 3647, 50 Stone Road East, Guelph N1G 2 W1, ON, Canada. aviloria@uoguelph.ca.

Cancer Cell International
|March 4, 2014
PubMed
Abstract

Insights

Par6 and TGFbeta receptor I activation are essential for TGFbeta-induced apoptosis in NMuMG cells. Par6 overexpression increases sensitivity to TGFbeta-induced apoptosis, impacting breast cancer prognosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The TGFbeta-Par6 pathway is implicated in loss of polarity and apoptosis in NMuMG cells.
  • Investigating the roles of Par6 and TGFbeta receptor I activation in TGFbeta-induced apoptosis and apico-basal polarity.
  • Focus on Par6 activation's effect on alpha6beta4 integrin and Nuclear Factor-kappaB (p65/RelA) activation.

Purpose of the Study:

  • To elucidate the specific contributions of Par6 and TGFbeta receptor I activation to TGFbeta-induced apoptosis.
  • To examine how Par6 activation influences alpha6beta4 integrin expression and localization.
  • To assess the impact on p65/RelA activation in the context of polarity changes and apoptosis.

Main Methods:

  • Utilized immunoblotting and immunofluorescence in NMuMG cell cultures (monolayer and 3D).
  • Assessed apoptosis, integrin expression/localization (alpha6, beta4, beta1), and p65/RelA phosphorylation/localization.
  • Quantified results via band densitometry or percentage of phenotypic 3D structures; analyzed using two-way ANOVA.

Main Results:

  • Blocking Par6 activation inhibited TGFbeta-induced apoptosis.
  • Par6 overactivation enhanced TGFbeta-induced apoptosis, particularly after prolonged exposure.
  • TGFbeta treatment altered alpha6beta4 integrin localization in 3D cultures, dependent on Par6 and TGFbeta receptor I activation, correlating with apoptosis.

Conclusions:

  • Both Par6 and TGFbeta receptor I activation are necessary for TGFbeta-induced apoptosis.
  • Endogenous Par6 levels may determine TGFbeta's role as pro-apoptotic or pro-survival factor in breast cancer.
  • Findings could aid in predicting patient prognosis and therapy response.

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