The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca2+ flux from the endoplasmic reticulum to mitochondria

Abstract

Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca2+ signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemination of TNBC cells. The molecular mechanism underlying CD95-mediated cell migration remains unknown. Here, we present genetic and pharmacologic evidence that the anti-apoptotic molecules BclxL and Bcl-2 and the pro-apoptotic factors BAD and BID cooperate to promote migration of TNBC cells stimulated with cl-CD95L. BclxL was distributed in both endoplasmic reticulum (ER) and mitochondrion membranes. The mitochondrion-localized isoform promoted cell migration by interacting with voltage-dependent anion channel 1 to orchestrate Ca2+ transfer from the ER to mitochondria in a BH3-dependent manner. Mitochondrial Ca2+ uniporter contributed to this flux, which favored ATP production and cell migration. In conclusion, this study reveals a novel molecular mechanism controlled by BclxL to promote cancer cell migration and supports the use of BH3 mimetics as therapeutic options not only to kill tumor cells but also to prevent metastatic dissemination in TNBCs.

The Regulation of Tumor Cell Invasion and Metastasis by Endoplasmic Reticulum-to-Mitochondrial Ca2+ Transfer

“…Antiapoptotic Bcl-XL and MCL1 both bind to VDAC1 and VDAC3 isoforms to promote mitochondrial Ca 2+ uptake and drive cell migration ( 77 – 80 ). Importantly, disrupting the Bcl-XL-VDAC and MCL1-VDAC interactions was found to inhibit migration of triple negative breast cancer cells ( 80 ) and non-small cell lung carcinoma cells, respectively ( 78 ). These data raise the possibility of suppressing invasion and metastasis by targeting VDAC-Bcl-2 protein interactions.…”

Extracorporeal Photopheresis: A Case of Immunotherapy Ahead of Its Time

“…In fact, 2 studies carried out in patients with systemic scleroderma showed that blood drawn 1 day after ECP had a high frequency of CD4 T cells with a high expression of CD95, a major regulator of extrinsic apoptosis [31, 32]. In vitro studies suggest that CD95 can cooperate with Bcl-xL and Bcl-2 to mobilize Ca2+ inside the mitochondria [33]. In mouse epidermal cells, exposure to 8-MOP/UVA results in p53 stabilization and nuclear translocation that triggers CD95 expression as early as 48 h after irradiation [34, 35].…”

Mitochondrial Involvement in Migration, Invasion and Metastasis

“…Other proteins localized to MAMs are VDAC and IP3R, the action of which is dependent on Bcl-2 family proteins and, in addition to their role in apoptosis, partly regulate Ca 2+ signaling via their complex with MAM proteins (Monaco et al, 2015;Bittremieux et al, 2019). Anti-apoptotic family members Bcl-2, Bcl-XL, and Mcl-1 bind to VDACs and suppress mitochondrial Ca 2+ transport that in turn supports cell migration and invasion (Huang et al, 2013(Huang et al, , 2014Fouqué et al, 2016). Both Bcl-2 and Bcl-XL interact with VDAC1 through BH4 domain; however, Bcl-XL BH4 is more effective than Bcl-2-BH4 in targeting VDAC1 activity (Monaco et al, 2015).…”

“…Both Bcl-2 and Bcl-XL interact with VDAC1 through BH4 domain; however, Bcl-XL BH4 is more effective than Bcl-2-BH4 in targeting VDAC1 activity (Monaco et al, 2015). Dissociation between these anti-apoptotic Bcl-2 family members and VDACs results in decreased migration of TNBC (Fouqué et al, 2016) and NSCLC cells (Huang et al, 2014). Bcl-2 family proteins could also interact with IP3R suppressing Ca 2+ -release.…”