Intrinsic, pro-apoptotic effects of IGFBP-3 on breast cancer cells are reversible: involvement of PKA, Rho, and ceramide

Claire M Perks, Carla Burrows, Jeffrey M P Holly

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)
194 Downloads (Pure)

Abstract

We established previously that IGFBP-3 could exert positive or negative effects on cell function depending upon the extracellular matrix composition and by interacting with integrin signaling. To elicit its pro-apoptotic effects IGFBP-3 bound to caveolin-1 and the beta 1 integrin receptor and increased their association culminating in MAPK activation. Disruption of these complexes or blocking the beta 1 integrin receptor reversed these intrinsic actions of IGFBP-3. In this study we have examined the signaling pathway between integrin receptor binding and MAPK activation that mediates the intrinsic, pro-apoptotic actions of IGFBP-3. We found on inhibiting protein kinase A (PKA), Rho associated kinase (ROCK), and ceramide, the accentuating effects of IGFBP-3 on apoptotic triggers were reversed, such that IGFBP-3 then conferred cell survival. We established that IGFBP-3 activated Rho, the upstream regulator of ROCK and that beta1 integrin and PKA were upstream of Rho activation, whereas the involvement of ceramide was downstream. The beta 1 integrin, PKA, Rho, and ceramide were all upstream of MAPK activation. These data highlight key components involved in the pro-apoptotic effects of IGFBP-3 and that inhibiting them leads to a reversal in the action of IGFBP-3.
Translated title of the contributionIntrinsic, pro-apoptotic effects of IGFBP-3 on breast cancer cells are reversible: involvement of PKA, Rho, and ceramide
Original languageEnglish
Article number13
Number of pages12
JournalFrontiers in Endocrinology
Volume2
DOIs
Publication statusPublished - 16 May 2011

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