alpha6beta4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-kappaB-dependent resistance to apoptosis in 3D mammary acini.

Abstract

Malignant transformation and multidrug resistance are linked to resistance to apoptosis, yet the molecular mechanisms that mediate tumor survival remain poorly understood. Because the stroma can influence tumor behavior by regulating the tissue phenotype, we explored the role of extracellular matrix signaling and tissue organization in epithelial survival. We report that elevated (alpha6)beta4 integrin-dependent Rac-Pak1 signaling supports resistance to apoptosis in mammary acini by permitting stress-dependent activation of the p65 subunit of NF-kappaB through Pak1. We found that inhibiting Pak1 through expression of N17Rac or PID compromises NF-kappaB activation and renders mammary acini sensitive to death, but that resistance to apoptosis could be restored to these structures by overexpressing wild-type NF-kappaB p65. We also observed that acini expressing elevated levels of Pak1 can activate p65 and survive death treatments, even in the absence of activated Rac, yet will die if activation of NF-kappaB is simultaneously inhibited through expression of IkappaBalphaM. Thus, mammary tissues can resist apoptotic stimuli by activating NF-kappaB through alpha6beta4 integrin-dependent Rac-Pak1 signaling. Our data emphasize the importance of the extracellular matrix stroma in tissue survival and suggest that alpha6beta4 integrin-dependent Rac stimulation of Pak1 could be an important mechanism mediating apoptosis-resistance in some breast tumors.

• Authors: Julie C Friedland, Johnathon N Lakins, Marcelo G Kazanietz, Jonathan Chernoff, David Boettiger, Valerie M Weaver
• Journal: Journal of cell science (J Cell Sci) Vol. 120 Issue Pt 20 Pg. 3700-12 (Oct 15 2007) ISSN: 0021-9533 [Print] England
• PMID: 17911169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Integrin alpha6beta4
• Transcription Factor RelA
• PAK1 protein, human
• Proto-Oncogene Proteins c-akt
• p21-Activated Kinases
• rac GTP-Binding Proteins

Topics

• Apoptosis
• Enzyme Activation
• Humans
• Integrin alpha6beta4 (metabolism)
• Mammary Glands, Human (cytology, metabolism, physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Transcription Factor RelA (metabolism)
• p21-Activated Kinases (metabolism)
• rac GTP-Binding Proteins (metabolism)