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 (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 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 Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells

2017 ◽  
Vol 18 (7) ◽  
pp. 1353 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Wei-An Chang ◽  
Pei-Hsun Tsai ◽  
Cheng-Ying Wu ◽  
Ya-Wen Ho ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
Apoptosis Inducing Factor

scholarly journals Subamolide A Induces Mitotic Catastrophe Accompanied by Apoptosis in Human Lung Cancer Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Jen-Yu Hung ◽  
Ching-Wen Wen ◽  
Ya-Ling Hsu ◽  
En-Shyh Lin ◽  
Ming-Shyan Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Nonsmall Cell Lung Cancer ◽  
Mitotic Catastrophe ◽  
Lung Cancer Cell ◽  
Atf3 Expression

This study investigated the anticancer effects of subamolide A (Sub-A), isolated fromCinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS) production and decreased glutathione level. The elevated ROS triggered the activation of ataxia-telangiectasia mutation (ATM), which further enhanced the ATF3 upregulation and subsequently enhanced p53 function by phosphorylation at Serine 15 and Serine 392. The antioxidant, EUK8, significantly decreased mitotic catastrophe by inhibiting ATM activation, ATF3 expression, and p53 phosphorylation. The reduction of ATM and ATF3 expression by shRNA decreased Sub-A-mediated p53 phosphorylation and mitotic catastrophe. Sub-A also caused a dramatic 70% reduction in tumor size in an animal model. Taken together, cell death of lung cancer cells in response to Sub-A is dependent on ROS generation, which triggers mitotic catastrophe followed by apoptosis. Therefore, Sub-A may be a novel anticancer agent for the treatment of nonsmall cell lung cancer.

scholarly journals Chitosan-Coated Gold Nanoparticles Induce Low Cytotoxicity and Low ROS Production in Primary Leucocytes, Independent of Their Proliferative Status

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 942
Author(s):  
Helen Yarimet Lorenzo-Anota ◽  
Diana G. Zarate-Triviño ◽  
Jorge Alberto Uribe-Echeverría ◽  
Andrea Ávila-Ávila ◽  
José Raúl Rangel-López ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Lymphoid Cells ◽  
Ros Production ◽  
Biomedical Sciences ◽  
Peripheral Blood Mononuclear

(1) Background: Chitosan-coated gold nanoparticles (CH-AuNPs) have important theranostic applications in biomedical sciences, including cancer research. However, although cell cytotoxicity has been studied in cancerous cells, little is known about their effect in proliferating primary leukocytes. Here, we assessed the effect of CH-AuNPs and the implication of ROS on non-cancerous endothelial and fibroblast cell lines and in proliferative lymphoid cells. (2) Methods: The Turkevich method was used to synthetize gold nanoparticles. We tested cell viability, cell death, ROS production, and cell cycle in primary lymphoid cells, compared with non-cancer and cancer cell lines. Concanavalin A (ConA) or lipopolysaccharide (LPS) were used to induce proliferation on lymphoid cells. (3) Results: CH-AuNPs presented high cytotoxicity and ROS production against cancer cells compared to non-cancer cells; they also induced a different pattern of ROS production in peripheral blood mononuclear cells (PBMCs). No significant cell-death difference was found in PBMCs, splenic mononuclear cells, and bone marrow cells (BMC) with or without a proliferative stimuli. (4) Conclusions: Taken together, our results highlight the selectivity of CH-AuNPs to cancer cells, discarding a consistent cytotoxicity upon proliferative cells including endothelial, fibroblast, and lymphoid cells, and suggest their application in cancer treatment without affecting immune cells.

scholarly journals Cytotoxicity and Apoptosis Effects of Curcumin Analogue (2E,6E)-2,6-Bis(2,3-Dimethoxybenzylidine) Cyclohexanone (DMCH) on Human Colon Cancer Cells HT29 and SW620 In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1261
Author(s):  
Nurul Fattin Che Rahim ◽  
Yazmin Hussin ◽  
Muhammad Nazirul Mubin Aziz ◽  
Nurul Elyani Mohamad ◽  
Swee Keong Yeap ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Curcuma Longa ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Sw620 Cell

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012–2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC50) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.

scholarly journals Targeting AKT/mTOR and Bcl-2 for Autophagic and Apoptosis Cell Death in Lung Cancer: Novel Activity of a Polyphenol Compound

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 534
Author(s):  
Sucharat Tungsukruthai ◽  
Onrapak Reamtong ◽  
Sittiruk Roytrakul ◽  
Suchada Sukrong ◽  
Chanida Vinayanwattikun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Proteomic Analysis ◽  
Interaction Analysis ◽  
Time Dependent ◽  
The Novel ◽  
Protein Protein Interaction ◽  
Autophagy Induction ◽  
Acidic Vesicle

Autophagic cell death (ACD) is an alternative death mechanism in resistant malignant cancer cells. In this study, we demonstrated how polyphenol stilbene compound PE5 exhibits potent ACD-promoting activity in lung cancer cells that may offer an opportunity for novel cancer treatment. Cell death caused by PE5 was found to be concomitant with dramatic autophagy induction, as indicated by acidic vesicle staining, autophagosome, and the LC3 conversion. We further confirmed that the main death induction caused by PE5 was via ACD, since the co-treatment with an autophagy inhibitor could reverse PE5-mediated cell death. Furthermore, the defined mechanism of action and upstream regulatory signals were identified using proteomic analysis. Time-dependent proteomic analysis showed that PE5 affected 2142 and 1996 proteins after 12 and 24 h of treatment, respectively. The crosstalk network comprising 128 proteins that control apoptosis and 25 proteins involved in autophagy was identified. Protein–protein interaction analysis further indicated that the induction of ACD was via AKT/mTOR and Bcl-2 suppression. Western blot analysis confirmed that the active forms of AKT, mTOR, and Bcl-2 were decreased in PE5-treated cells. Taken together, we demonstrated the novel mechanism of PE5 in shifting autophagy toward cell death induction by targeting AKT/mTOR and Bcl-2 suppression.

Sign in / Sign up

Export Citation Format

Share Document