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.
In summary, our results suggest that HO-1 can decrease H/R-induced myocardiac cell apoptosis; the mechanism may be related to the activation of the Akt signaling pathway and, furthermore, to the inhibition of the JNK/c-Jun/caspase-3 signaling pathway.
Human ovarian cancer models were established in nude mice by transplanting SKOV(3) cells, and then tumors were exposed to high-intensity electric pulses with a voltage 1000 V, frequency of 1000 Hz, and duration of 250 ns for 1 min. Mitochondria permeability transition pore (PTP) was inspected by cofocal microscope; cytochrome C (Cyt C) and apoptosis-induced factor (AIF) were determined by immunohistochemistry; and voltage-dependent anion channel (VDAC) was measured by immunofluorescence. High-intensity electric pulses exposure led to increases of PTP, Cyt C, and AIF and a decrease of VDAC. These findings revealed that high-intensity electric pulses activated mitochondria electroporation, apoptosis was realized via mitochondria pathway.
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