Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death

A series of novel camphor-based pyrimidine derivatives were synthesized and characterized. We found the compound 3f exhibited strongest anti-tumor activity via ROS-mediated mitochondrial apoptosis pathway.

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Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway through inhibiting cytosolic ferritin and inducing chromotin autophagy

10.21203/rs.2.22978/v3 ◽

2020 ◽

Author(s):

Qingyuan Feng ◽

Xuzhao Bian ◽

Xuan Liu ◽

Ying Wang ◽

Huiting Zhou ◽

...

Keyword(s):

Cell Death ◽

Western Blot ◽

Cancer Cell ◽

Malignant Tumors ◽

Mitochondrial Damage ◽

Arginine Deiminase ◽

Immunofluorescent Staining ◽

Apoptosis Pathway ◽

P53 Expression ◽

Cancer Cell Death

Abstract Background：Based on its low toxicity, arginine starvation therapy has the potential to treat those malignant tumors that can’t be treated by surgery. Arginine deiminase (ADI) gene is indicated to be an ideal cancer-suppressor gene. ADI expressed in cytosol displays higher oncolytic efficiency than ADI-PEG20 (Pegylated Arginine Deiminase by PEG 20,000). However, it is still unknown whether cytosolic ADI has the same function mechanism as ADI-PEG20 or other underlying mechanisms in cells.Methods: The interaction of ADI and other protein factors was screened by yeast hybrid, and verified by co-immunoprecipitation and immunofluorescent staining. The effect of ADI inhibiting ferritin light-chain domain (FTL) on mitochondrial damage was evaluated by site-directed mutation and flow cytometry. The apoptosis pathway of mitochondria control was analyzed by Western Blot and real-time PCR experiments. The effect of p53 expression on cancer cell death was assessed by siTP53 transfection. The chromatin autophagy was explored by immunofluorescent staining and Western Blot.Results: ADI expressed in cytosol inhibited the activity of cytosolic ferritin through interacting with FTL. The inactive mutant of ADI still induced the apoptosis in certain cell lines of ASS- through mitochondrial damage. Arginine starvation also induced the increased expression of p53 and p53AIP1, which aggravate cellular mitochondrial damage. Chromatin autophagy appeared at the later stage of arginine starvation. DNA damage came along with the whole process of arginine starvation. Histone 3 (H3) was found in autophagosomes, which implied that cancer cells try to utilize the arginine in histones to survive during arginine starvation. Conclusions: Mitochondrial damage is the major mechanism of cell death induced by cytosolic ADI. Chromatophagy accumulations not only drive cancer cell to utilize histone arginine but also speed up cancer cell death at the later time point of arginine starvation.

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Arginine deimimase expressed in vivo activates the mitochondrial apoptosis pathway through inhibiting cytosolic ferritin and inducing chromotin autophagy

10.21203/rs.2.22978/v1 ◽

2020 ◽

Author(s):

Qingyuan Feng ◽

Xuzhao Bian ◽

Xuan Liu ◽

Ying Wang ◽

Huiting Zhou ◽

...

Keyword(s):

Cell Death ◽

Western Blot ◽

Cancer Cell ◽

Malignant Tumors ◽

Arginine Deiminase ◽

Immunofluorescent Staining ◽

Apoptosis Pathway ◽

P53 Expression ◽

Cancer Cell Death

Abstract BackgroundBased on its low toxicity, arginine starvation therapy has the potential to treat those malignant tumors that can’t be treated by surgery. Arginine deiminase (ADI) gene is indicated to be an idea cancer-suppressor gene. ADI expressed in vivo displays higher oncolytic efficiency than ADI-PEG20 (Pegylated Arginine Deiminase by PEG 20,000)[1]. However, it is still unknown whether cytosolic ADI has the same function mechanism as ADI-PEG20 or other underlying mechanisms in cells.MethodsThe interaction of ADI and other protein factors was screened by yeast hybrid, and verified by co-immunoprecipitation and immunofluorescent staining. The effect of ADI inhibiting ferritin light-chain domain (FTL) on mitochondria damage was evaluated by site-directed mutation and flow cytometry. The apoptosis pathway of mitochondria control was analyzed by Western Blot and real-time PCR. The effect of p53 expression on cancer cell death was assessed by siTP53 transfection. The chromatin autophagy was explored by immunofluorescent staining and Western Blot.ResultsADI expressed in vivo inhibited the activity of cytosolic ferritin through interacting with FTL. The inactive mutant of ADI still aroused the apoptosis of some cells through mitochondria damage. Arginine starvation also induced the expression increase of p53 and p53AIP1, which aggravate cellular mitochondria damage. Chromatin autophagy appeared at the later stage of arginine starvation. DNA damage came along with the whole process of arginine starvation. Histone 3 (H3) was found in autophagosomes, which implied that cancer cells try to utilize the arginine in histones to survive during arginine starvation.Conclusions: Mitochondria damage is the major mechanism for ADI expressed in vivo to induce cancer cell death. Chromatophagy accumulations not only drive cancer cell to utilize histone arginine but also speed up cancer cell death at the later time point of arginine starvation.

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Intracellular expression of arginine deimimase activates the mitochondrial apoptosis pathway through inhibiting cytosolic ferritin and inducing chromotin autophagy

10.21203/rs.2.22978/v2 ◽

2020 ◽

Author(s):

Qingyuan Feng ◽

Xuzhao Bian ◽

Xuan Liu ◽

Ying Wang ◽

Huiting Zhou ◽

...

Keyword(s):

Cell Death ◽

Western Blot ◽

Cancer Cell ◽

Malignant Tumors ◽

Arginine Deiminase ◽

Immunofluorescent Staining ◽

Apoptosis Pathway ◽

P53 Expression ◽

Cancer Cell Death ◽

Arginine Deprivation

Abstract Background Based on its low toxicity, arginine starvation therapy has the potential to treat those malignant tumors that can’t be treated by surgery. Arginine deiminase (ADI; EC 3.5.3.6) gene is indicated to be an ideal cancer-suppressor gene. ADI expressed in cytosol displayed higher oncolytic efficiency than ADI-PEG20 (Pegylated Arginine Deiminase by PEG 20,000)[1]. However, it is still unknown whether cytosolic ADI has the same function mechanism as ADI-PEG20 or other underlying mechanisms in cells. Methods The interaction of ADI and other protein factors was screened by yeast hybrid, and verified by co-immunoprecipitation and immunofluorescent staining. The effect of ADI inhibiting ferritin light-chain domain (FTL) on mitochondria damage was evaluated by site-directed mutation and flow cytometry. The apoptosis pathway of mitochondria control was analyzed by Western Blot and real-time PCR. The effect of p53 expression on cancer cell death was assessed by siTP53 transfection. The chromatin autophagy was explored by immunofluorescent staining and Western Blot. Results ADI expressed in cytosol inhibited the activity of cytosolic ferritin through interacting with FTL. The inactive mutant of ADI still aroused the apoptosis of some cells through mitochondria damage. Arginine deprivation also induced the expression increase of p53 and p53AIP1, which aggravated cellular mitochondria damage. Chromatin autophagy appeared at the later stage of arginine deprivation. DNA damage came along with the whole process of arginine starvation. Histone 3 (H3) was found in autophagosomes, which implied that cancer cells try to utilize the arginine in histones to survive during arginine starvation. Conclusions Mitochondria damage is the major mechanism for ADI expressed in cytosol to induce cancer cell death. Chromatophagy accumulation not only drives cancer cell to utilize histone arginine but also speeds up cancer cell death at the later time point of arginine deprivation.

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Cytotoxic effects of SMAC-mimetic compound LCL161 in head and neck cancer cell lines

Clinical Oral Investigations ◽

10.1007/s00784-016-1741-3 ◽

2016 ◽

Vol 20 (9) ◽

pp. 2325-2332 ◽

Cited By ~ 11

Author(s):

Roman C. Brands ◽

Franziska Herbst ◽

Stefan Hartmann ◽

Axel Seher ◽

Christian Linz ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Cell Lines ◽

Cancer Cell ◽

Neck Cancer ◽

Cancer Cell Lines ◽

Cytotoxic Effects ◽

Smac Mimetic ◽

Smac Mimetic Compound ◽

Mimetic Compound

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Recovering Drug-Induced Apoptosis Subnetwork from Connectivity Map Data

BioMed Research International ◽

10.1155/2015/708563 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Jiyang Yu ◽

Preeti Putcha ◽

Jose M. Silva

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Specific Cell ◽

Connectivity Map ◽

Drug Induced ◽

Significant Differential Expression ◽

Apoptosis Pathway ◽

Cell Death Pathways ◽

Intrinsic Apoptosis Pathway ◽

Extrinsic Apoptosis

The Connectivity Map (CMAP) project profiled human cancer cell lines exposed to a library of anticancer compounds with the goal of connecting cancer with underlying genes and potential treatments. Since the therapeutic goal of most anticancer drugs is to induce tumor-selective apoptosis, it is critical to understand the specific cell death pathways triggered by drugs. This can help to better understand the mechanism of how cancer cells respond to chemical stimulations and improve the treatment of human tumors. In this study, using CMAP microarray data from breast cancer cell line MCF7, we applied a Gaussian Bayesian network modeling approach and identified apoptosis as a major drug-induced cellular-pathway. We then focused on 13 apoptotic genes that showed significant differential expression across all drug-perturbed samples to reconstruct the apoptosis network. In our predicted subnetwork, 9 out of 15 high-confidence interactions were validated in the literature, and our inferred network captured two major cell death pathways by identifying BCL2L11 and PMAIP1 as key interacting players for the intrinsic apoptosis pathway and TAXBP1 and TNFAIP3 for the extrinsic apoptosis pathway. Our inferred apoptosis network also suggested the role of BCL2L11 and TNFAIP3 as “gateway” genes in the drug-induced intrinsic and extrinsic apoptosis pathways.

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