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p14ARF induces apoptosis via an entirely caspase-3-dependent mitochondrial amplification loop

Item Type:Article
Title:p14ARF induces apoptosis via an entirely caspase-3-dependent mitochondrial amplification loop
Creators Name:Milojkovic, A. and Hemmati, P.G. and Mueer, A. and Overkamp, T. and Chumduri, C. and Jaenicke, R.U. and Gillissen, B. and Daniel, P.T.
Abstract:The p14(ARF) tumor suppressor triggers cell death or cell cycle arrest upon oncogenic stress. In MCF-7 breast carcinoma cells, expression of the tumor suppressor gene p14(ARF) fails to trigger apoptosis but induces an arrest in the G1 and, to a lesser extent, in the G2 phase in the cell division cycle. Here, inhibition of cell cycle arrest resulted in apoptosis induction in caspase-3 proficient MCF-7 cells upon expression of p14(ARF). This occurred in the absence of S-phase progression or mitotic entry. In contrast, syngeneic, caspase-3-deficient MCF-7 cells remained entirely resistant to p14(ARF)-induced apoptosis. Thus, cell cycle checkpoint abrogation overcomes resistance to p14(ARF)-induced cell death and promotes cell death via a caspase-3-dependent pathway. Cell death coincided with dissipation of the mitochondrial membrane potential, release of cytochrome c, and was inhibitable by pan-caspase inhibitors and the caspase-3/7 inhibitor zDEVD-fmk. Of note, mitochondrial events of apoptosis execution depended entirely on caspase-3 proficiency indicating that caspase-3 either acts "up-stream" of the mitochondria in a "non-canonical" pathway or mediates a mitochondrial feedback loop to amplify the apoptotic caspase signal in p14(ARF)-induced stress signaling.
Keywords:p14(ARF), Caspase-3, Apoptosis, Mitochondria
Source:International Journal of Cancer
Page Range:2551-2562
Date:1 December 2013
Official Publication:https://doi.org/10.1002/ijc.28279
PubMed:View item in PubMed

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