BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca2+-dependent mPTP opening

Martijn Kerkhofs, Rita La Rovere, Kirsten Welkenhuysen, Ann Janssens, Peter Vandenberghe, Muniswamy Madesh, Jan B. Parys, Geert Bultynck

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Anti-apoptotic Bcl-2 critically controls cell death by neutralizing pro-apoptotic Bcl-2-family members at the mitochondria. Bcl-2 proteins also act at the endoplasmic reticulum, the main intracellular Ca2+-storage organelle, where they inhibit IP3 receptors (IP3R) and prevent pro-apoptotic Ca2+-signaling events. IP3R channels are targeted by the BH4 domain of Bcl-2. Some cancer types rely on the IP3R-Bcl-2 interaction for survival. We previously developed a cell-permeable, BH4-domain-targeting peptide that can abrogate Bcl-2′s inhibitory action on IP3Rs, named Bcl-2 IP3 receptor disrupter-2 (BIRD-2). This peptide kills several Bcl-2-dependent cancer cell types, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukaemia (CLL) cells, by eliciting intracellular Ca2+ signalling. However, the exact mechanisms by which these excessive Ca2+ signals triggered by BIRD-2 provoke cancer cell death remain elusive. Here, we demonstrate in DLBCL that although BIRD-2 activates caspase 3/7 and provokes cell death in a caspase-dependent manner, the cell death is independent of pro-apoptotic Bcl-2-family members, Bim, Bax and Bak. Instead, BIRD-2 provokes mitochondrial Ca2+ overload that is rapidly followed by opening of the mitochondrial permeability transition pore (mPTP). Inhibiting mitochondrial Ca2+ overload using Ru265, an inhibitor of the mitochondrial Ca2+ uniporter complex counteracts BIRD-2-induced cancer cell death. Finally, we validated our findings in primary CLL patient samples where BIRD-2 provoked mitochondrial Ca2+ overload and Ru265 counteracted BIRD-2-induced cell death. Overall, this work reveals the mechanisms by which BIRD-2 provokes cell death, which occurs via mitochondrial Ca2+ overload but acts independently of pro-apoptotic Bcl-2-family members.

Original languageEnglish (US)
Article number102333
JournalCell Calcium
Volume94
DOIs
StatePublished - Mar 2021

Keywords

  • Apoptosis
  • B-cell lymphoma 2
  • Calcium signaling
  • Mitochondrial permeability transition pore
  • Targeted therapy

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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