scholarly journals Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce AIF-caspase independent cell death.

2020 ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Elaine Langenfeld ◽  
Danea Glover ◽  
Michael Scott ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Nuclear Translocation ◽  
Bmp Signaling ◽  
Lung Carcinomas ◽  
Bmp Receptor ◽  
Cell Death Pathway ◽  
Morphogenetic Protein ◽  
Receptor Inhibitor

Abstract Background: BMP is an evolutionary 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 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 carcinomas (NSCLC) cell lines. Validation experiments were performed on five passage 0 primary NSCLC.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. Ym155 mediated cell death is not caused by the inhibition of survivin but involves Ym155 binding to mitochondrial DNA leading to depletion of ATP. 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 causing DNA double stranded breaks independent of caspase activation, which occurs 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 evolutionary conserved cell death pathway that has never been targeted to induce cell death in cancer cells. These studies provide mechanistic insight how to target AIF caspase-independent cell death using BMP inhibitors.

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

2020 ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Elaine Langenfeld ◽  
Danea Glover ◽  
Michael Scott ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Bmp Signaling ◽  
Bmp Receptor ◽  
Morphogenetic Protein ◽  
Evolutionarily Conserved ◽  
Apoptosis Inducing Factor ◽  
Receptor Inhibitor

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.

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

2020 ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Elaine Langenfeld ◽  
Danea Glover ◽  
Michael Scott ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Bmp Signaling ◽  
Bmp Receptor ◽  
Morphogenetic Protein ◽  
Evolutionarily Conserved ◽  
Apoptosis Inducing Factor ◽  
Receptor Inhibitor

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.

scholarly journals Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Arindam Mondal ◽  
Rachel NeMoyer ◽  
Mehul Vora ◽  
Logan Napoli ◽  
Zoya Syed ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Survival ◽  
Cancer Cells ◽  
Bone Morphogenetic Protein ◽  
Neurological Diseases ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein

Abstract Background Recent studies have shown that bone morphogenetic protein receptor 2 (BMPR2) regulates cell survival signaling events in cancer cells independent of the BMP type 1 receptor (BMPR1) or the Smad-1/5 transcription factor. Mutations in BMPR2 trafficking proteins leads to overactive BMP signaling, which leads to neurological diseases caused by BMPR2 stabilization of the microtubules. It is not known whether BMPR2 regulates the microtubules in cancer cells and what effect this has on cell survival. It is also not known whether alterations in BMPR2 trafficking effects activity and response to BMPR2 inhibitors. Methods We utilized BMPR2 siRNA and the BMP receptor inhibitors JL5 and Ym155, which decrease BMPR2 signaling and cause its mislocalization to the cytoplasm. Using the JL5 resistant MDA-MD-468 cell line and sensitive lung cancer cell lines, we examined the effects of BMPR2 inhibition on BMPR2 mislocalization to the cytoplasm, microtubule destabilization, lysosome activation and cell survival. Results We show that the inhibition of BMPR2 destabilizes the microtubules. Destabilization of the microtubules leads to the activation of the lysosomes. Activated lysosomes further decreases BMPR2 signaling by causing it to mislocalizated to the cytoplasm and/or lysosome for degradation. Inhibition of the lysosomes with chloroquine attenuates BMPR2 trafficking to the lysosome and cell death induced by BMPR2 inhibitors. Furthermore, in MDA-MD-468 cells that are resistant to JL5 induced cell death, BMPR2 was predominately located in the cytoplasm. BMPR2 failed to localize to the cytoplasm and/or lysosome following treatment with JL5 and did not destabilize the microtubules or activate the lysosomes. Conclusions These studies reveal that the inhibition of BMPR2 destabilizes the microtubules promoting cell death of cancer cells that involves the activation of the lysosomes. Resistance to small molecules targeting BMPR2 may occur if the BMPR2 is localized predominantly to the cytoplasm and/or fails to localize to the lysosome for degradation.

scholarly journals MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival

2021 ◽  
Author(s):  
Othello Del Rosario ◽  
Karthik Suresh ◽  
Medha Kallem ◽  
Gayatri Singh ◽  
Anika Shah ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Caspase 3 ◽  
Nuclear Translocation ◽  
Carcinoma Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
Carcinoma Cell Lines

Non-small cell lung cancers demonstrate intrinsic resistance to cell death even in response to chemotherapy. Previous work suggested that defective nuclear translocation of active caspase 3 may play a role in resistance to cell death. Separately, our group has identified that mitogen activated protein kinase activated protein kinase 2 (MK2) is required for nuclear translocation of active caspase 3 in the execution of apoptosis. This study demonstrates a relatively low expression of MK2 in non-small cell lung carcinoma cell lines compared to small cell carcinoma cell lines. Further, overexpression of MK2 in non-small cell lung carcinoma cell lines results in increased caspase 3 activity and caspase 3 mediated cell death. Higher MK2 transcript levels were observed in patients with earlier-stage non-small cell lung cancer. Higher expression of MK2 is associated with better survival in patients with early stage non-small cell lung cancer across two independent clinical datasets. Using data sets spanning multiple cancer types, we observed improved survival with higher MK2 expression was unique to lung adenocarcinoma. Mechanistically, MK2 promotes nuclear translocation of caspase 3 leading to PARP1 cleavage and execution of cell death. While MK2 can directly phosphorylate caspase 3, neither phosphorylation status of caspase 3 nor the kinase activity of MK2 impacts caspase 3 activation, nuclear translocation and execution of cell death. Rather, a non-kinase function of MK2, specifically trafficking via its nuclear localization sequence, is required for caspase 3 mediated cell death. In summary this study highlights the importance of a non-enzymatic function of MK2 in the execution of apoptosis, which may be leveraged in the adjunctive treatment of NSCLC or other conditions where regulation of apoptosis is crucial.

scholarly journals DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lama Tarayrah-Ibraheim ◽  
Elital Chass Maurice ◽  
Guy Hadary ◽  
Sharon Ben-Hur ◽  
Alina Kolpakova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Germ Cells ◽  
Nuclear Translocation ◽  
Primordial Germ Cells ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Dnase Ii ◽  
Cell Death Pathway ◽  
Parp 1

AbstractDuring Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.

Modes of cell death induced by novel tetrahydroisoquinolinone-based analogues in breast- and lung cancer cell lines

2016 ◽  
Vol 61 ◽  
pp. S57
Author(s):  
M. Verwey ◽  
A.M. Joubert ◽  
W. Dohle ◽  
B.V.L. Potter ◽  
A.E. Theron
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Lung Cancer Cell

Cyclin D1 antisense RNA destabilizes pRb and retards lung cancer cell growth

1997 ◽  
Vol 273 (5) ◽  
pp. L941-L949 ◽  
Author(s):  
Barbara Driscoll ◽  
Lingtao Wu ◽  
Susan Buckley ◽  
Frederick L. Hall ◽  
Kathryn D. Anderson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cyclin D ◽  
Lung Cancer Cell ◽  
Cancer Cell Growth ◽  
Transfected Cells ◽  
The Impact

To investigate the role of cyclin D1 in the regulation of lung cancer cell growth, we created five stably transfected cell lines carrying a cyclin D1 antisense construct. The transfected cells exhibited a marked decrease in the rate of cell growth, in contrast to the original lines (A549 and NCI-H441). The expression of several cell cycle-regulating proteins, including cyclin A, the cyclin-dependent kinases (cdk) 2 and cdk4, in addition to cyclin D1 itself, was markedly decreased. The expression of one cdk inhibitor, p21WAF1/CIP1, increased in the A549-derived cell lines. A specific target of cyclin D1 activity, the growth-suppressing product of the retinoblastoma gene, pRb, exhibited decreased expression and a decreased level of phosphorylation in the transfected cells. Decreased expression of pRb due to a significant increase in its turnover rate suggested that the stability of the protein may depend on phosphorylation by cyclin D1-dependent cdk activity. In addition to the impact on pRb stability, decreased expression of cyclin D1 induced susceptibility to cell death after withdrawal of exogenous growth factors in the antisense transfected cell lines, a response that was not observed in the original cancer cell lines. We conclude that abrogation of cyclin D1 overexpression in lung cancer cells disrupts several key pathways that are required for uncontrolled cell growth and induces those that lead to cell death after growth factor deprivation. Therefore, we speculate that use of antisense cyclin D1 expression in appropriate gene vectors could be a useful method for retarding lung cancer cell growth in accessible tumors such as those of the lung epithelium.

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