The process of “programmed cell suicide”, referred to as apoptosis is classically controlled by the B-cell lymphoma-2 (Bcl-2) family members, a group of intracellular proteins with a pro-death (e.g. Bax and Bak) or anti-death (e.g. Bcl-2, Bcl-Xl) role. Thus, the excessive expression of the protective Bcl-2 members is a typical trademark associated with the survival advantage of many hematological as well as solid cancers [1-2]. The recently identified interaction of the anti-apoptotic Bcl-2 protein with the inositol 1,4,5-trisphosphate receptor (IP3R), a ubiquitous Ca2+-release channel in the endoplasmic reticulum (ER), represents one of the stratagems by which Bcl-2 extends the life-span of cancer cells [3]. Bcl-2 can thereby inhibit the IP3R-mediated Ca2+ firing and reduce the lethal Ca2+ transfer from the ER to the mitochondria. The only Bcl-2 molecular component essential and sufficient for this inhibitory activity on the IP3R is the homology domain 4 (Bcl-2-BH4) [4].

In our study, we first revealed that although Bcl-2 shares high structural and biochemical similarity with Bcl-Xl, its closest protein relative, the latter could not curb the pro-apoptotic ER-Ca2+ discharge. This differential action of Bcl-2 versus Bcl-Xl on the IP3R could be attributable to one critical amino acid difference in their BH4 domains [5]. Furthermore, we found that BH4-Bcl-Xl, which is also able to protect against Ca2+-mediated apoptosis, acted downstream of IP3R signaling, by physically interacting with the voltage-dependent anion channel 1 (VDAC1), an outer mitochondrial Ca2+ gateway. Our findings opened novel avenues to selectively suppress malignant Bcl-2 or Bcl-Xl functions in cancer cells by targeting their BH4 domain biology. Accordingly, we screened for apoptosis induction a set of diffuse large-B-cell lymphoma cells (DL-BCL) treated with a cell-permeable version of a peptide that selectively antagonized Bcl-2-BH4's binding to the IP3R (IP3R-derived peptide: IDP). As a result, we observed that the most responsive subclasses of DL-BCL are also the ones that express the highest levels of the type 2 IP3R (IP3R2), which is the most sensitive isoform to IP3 signaling [6]. This is compatible with the higher metabolic needs of the DL-BCL, which in the responsive DL-BCL, was reflected in: 1) a general chronic activation of the B-cell receptor (BCR) signaling [7]; 2) an up-regulation of IP3R2 and 3) an addiction to Bcl-2 in order to suppress the potentially lethal IP3R hyperactivity.

Collectively, our work provided a better understanding of the molecular and functional conversation between the Ca2+channels at the ER/mitochondria interface and the Bcl-2/Bcl-Xl proteins. These new findings could lead to the development of more selective and safer peptidomimetics targeting the adaptive Ca2+-signaling dysregulation of cancer cells.

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Citation Format: Haidar Akl, Giovanni Monaco, Elke Decrock, Rita La Rovere, Kirsten Welkenhuyzen, Tomas Luyten, Santeri Kiviluoto, Tim Vervliet, Jordi Molgo, Ludwig Missiaen, Katsuhiko Mikoshiba, Luc Leybaert, Jan B. Parys, Humbert De Smedt, Clark W. Distelhorst, Geert Bultynck. The regulation of the ER-mitochondria-Ca2+ cross-talk by Bcl-2 and Bcl-XL: A new scenario for the development of selective tools in oncology? [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B42.