Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce Apoptosis-Inducing Factor (AIF) caspase independent cell death

Abstract

Background: Bone morphogenetic protein (BMP) is an evolutionarily conserved morphogen that is reactivated in lung carcinomas. BMP receptor inhibitors promote cell death of lung carcinomas by mechanisms not fully elucidated. The studies here reveal novel mechanisms by which the “survivin” inhibitor Ym155 in combination with the BMP receptor inhibitor JL5 synergistically induces death of lung cancer cells. Methods: This study examines the mechanism by which Ym155 in combination with JL5 downregulates BMP signaling and induces cell death of non-small cell lung carcinoma (NSCLC) cell lines. Validation experiments were performed on five passage 0 primary NSCLC cell lines. Results: We found that Ym155, which is reported to be a survivin inhibitor, potently inhibits BMP signaling by causing BMPR2 mislocalization into the cytoplasm and its decreased expression. The combination of Ym155 and the BMP receptor inhibitor JL5 synergistically causes the downregulation of BMP Smad-1/5 dependent and independent signaling and the induction of cell death of lung cancer cell lines and primary lung tumors. Cell death involves the nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. This causes DNA double stranded breaks independent of caspase activation, which occur only when JL5 and Ym155 are used in combination. Knockdown of BMPR2 together with Ym155 also induced AIF localization to the nucleus. Conclusions: These studies suggest that inhibition of BMPR2 together with Ym155 can induce AIF caspase-independent cell death. AIF caspase-independent cell is an evolutionarily conserved cell death pathway that has never been targeted to induce cell death in cancer cells. These studies provide mechanistic insight of how to target AIF caspase-independent cell death using BMP inhibitors.

Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells

“…Ym155 inhibits BMP signaling in lung cancer cells at low nanomolar concentrations 15 . We recently showed in both lung cancer cells and C elegans that AMPK suppresses BMP signaling 16 , 17 Ym155 was also shown to synergize with BMP inhibition to induce AIF caspase-independent cell death that involves the activation of AMPK 16 . Ym155, atpenin, cisplatin, and phenformin all activated AMPK and suppressed BMP signaling in lung cancer cells.…”

“…The mechanism by which Ym155 decreases BMP signaling is not known. Recently, AMPK was shown to suppress BMP signaling in lung cancer cells and C elegans 16 , 17 . The combination of BMP small molecule inhibitors with Ym155 synergistically induced caspase-independent cell death that involved apoptosis inducing factor (AIF) being released from the mitochondria and localizing to chromosomal DNA.…”

Biological function, mediate cell death pathway and their potential regulated mechanisms for post-mortem muscle tenderization of PARP1: A review

“…Oxidative stress can cause DNA damage, and PARP1, a DNA damage receptor, is over-activated causing the occurrence of Parthanatos ( 49 , 50 ). As shown in Figure 4 , PARP1 is rapidly activated after the occurrence of DNA damage, and PAR polymer accumulates in the cells and consumes a large amount of NAD+, thus inhibiting the activity of the mitochondrial oxidative respiratory chain complex enzyme, blocking the tricarboxylic acid cycle pathway, impairing mitochondrial energy metabolism, and inducing the release of AIF from the mitochondria and its transfer to the nucleus ( 51 – 53 ). After AIF enters the nucleus, the large DNA fragment is degraded to a 50 kb fragment.…”