P14ARF induces apoptosis via an entirely caspase‐3‐dependent mitochondrial amplification loop. Issue 11 (1st August 2013)

• Record Type: Journal Article
• Authors: Milojkovic, Ana; Hemmati, Philipp G.; Müer, Annika; Overkamp, Tim; Chumduri, Cindrilla; Jänicke, Reiner U.; Gillissen, Bernd; Daniel, Peter T.
• Is Part Of: International journal of cancer. Volume 133:Issue 11(2013:Dec. 01)
• Page Start: 2551
• Page End: 2562
• Publication Date: 2013-08-01
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28279
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>via</italic> 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.</p> </abstract>