Figure 2: A graphic summary of targets in cancer cells altering IP₃R-mediated ER-mitochondrial Ca²⁺ fluxes.

A: Cancer cells are addicted to pro-survival ER-mitochondrial Ca²⁺ transfers, which promote the mitochondrial metabolism through Ca²⁺-dependent stimulation of TCA and OXPHOS and suppress autophagic flux. This not only serves for ATP production but also for anabolic pathways through the production of intermediate substrates to synthesize nucleotides. IP₃R function can be enhanced by anti-apoptotic/pro-survival proteins such as Bcl-X_L. B: Cancer cells also avoid pro-apoptotic ER-mitochondrial Ca²⁺ transfers. Excessive Ca²⁺ levels in the mitochondrial matrix lead to cell death via opening of the mPTP. Cancer cells can circumvent this by i. decreasing IP₃R levels or ii. modulate IP₃R function. PTEN competes with FBXL2, which can mark IP₃R for degradation by ubiquitination. Similarly, the oncogenic transcription factor STAT3 facilitates IP₃R degradation at the MAMs. Conversely, BAP1 interacts with and deubiquitinates IP₃R. Additionally, S1R binds and stabilizes IP₃R. Methylated PKM2 was observed to interact with IP₃R in the MAMs and to promote IP₃R downregulation. Note that the methylations of PKM2 are more complex than the single methyl group depicted here. PTEN negatively regulates PKB/Akt-dependent phosphorylation of IP₃Rs, this way promoting pro-apoptotic Ca²⁺ signaling in the MAMs. Additionally, Nox4 promotes PKB/Akt-mediated inhibitory IP₃R phosphorylation. Also, PML recruits PP2A to the MAMs, where it counteracts PKB/Akt activity. Moreover, several anti-apoptotic Bcl-2 proteins can inhibit IP₃R, either directly or in cooperation with phosphorylated IRBIT (as is the case for Bcl-2L10). Finally, HK2 negatively modulates pro-apoptotic IP₃R-driven Ca²⁺ fluxes. ER: Endoplasmic reticulum, MAM: Mitochondria-associated ER membrane, TCA: Tricarboxylic acid cycle, OXPHOS: oxidative phosphorylation, Ca²⁺: Calcium ion, K⁺: Potassium ion, IP₃R: Inositol 1,4,5-trisphosphate receptor type 1, GRP75: Glucose-regulated protein 75, VDAC1: Voltage dependent anion channel 1, MCU: Mitochondrial Ca²⁺ uniporter, BK_Cα: Calcium-activated potassium channel, Bcl-X_L: B-cell lymphoma extra-large, mPTP: Mitochondrial permeability transition pore, FBXL2: F-box/LRR-repeat protein 2, Bap1: Ubiquitin carboxyl-terminal hydrolase BAP1, PTEN: Phosphatase and tensin homolog, STAT3: Signal transducer and activator of transcription 3, S1R: Sigma-1 receptor, Bcl-2: B-cell lymphoma 2, Bcl-2L10: Bcl-2 like protein 10, Nox4: NADPH oxidase 4, PML: Promyelocytic leukemia protein, PP2A: Protein phosphatase 2A, IRBIT: IP₃R binding protein released with IP₃, PKB/Akt: Protein kinase B, HK2: Hexokinase 2, Ub: Ubiquitinylations, P: Phosphorylations, CH₃: Methylations.