Recent insights into apoptosis and toxic autophagy: The roles of MDA-7/IL-24, a multidimensional anti-cancer therapeutic

Emdad, Luni; Bhoopathi, Praveen; Talukdar, Sarmistha; Pradhan, Anjan K.; Sarkar, Devanand; Wang, Xiangyang; Das, Swadesh K.; Fisher, Paul B.

doi:10.1016/j.semcancer.2019.07.013

Cited by 60 publications

(54 citation statements)

References 214 publications

(390 reference statements)

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“…Similar studies also demonstrated that a deficiency of basal autophagy induced thyroid follicular epithelial cell death, 51 and autophagy played seminal roles for cells to adapt abdominal microenvironment in metastatic ovarian cancer 52 . Different from findings in these studies, Emdad et al 53 . systematically and comprehensively provided the conception of toxic autophagy, where excessive autophagy could promote type II cell death.…”

Section: Discussionmentioning

confidence: 96%

Crosstalk between let-7a-5p and BCL-xL in the Initiation of Toxic Autophagy in Lung Cancer

Duan

Tian

et al. 2019

Molecular Therapy - Oncolytics

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Autophagy is essential for cellular metabolism and plays pivotal roles in carcinogenesis, while excessive autophagy induces toxicity and cell death. Our previous studies have suggested that let-7a-5p/BCL-xL might regulate autophagy in lung cancer, but the regulatory mechanism is unclear. The central goal of the study was to figure out the role of let-7a-5p/BCL-xL in the initiation of autophagy and its effect on the migration, invasion, and proliferation of A549 cells as well as its therapeutic potential in lung cancer. Based on the genome-wide expression profiles of lung cancer, BCL-xL and let-7a-5p were found to be dysregulated and negatively correlated in lung adenocarcinoma, which was associated with the survival of lung cancer. The crosstalk between BCL-xL and let-7a-5p was then investigated using dual-luciferase reporter assay, and it was found to suppress the migration and invasion of A549 cells. Further, we found that the crosstalk between BCL-xL and let-7a-5p could lead to toxic autophagy and cell death through activating the PI3K-signaling pathway, which was independent of apoptosis or pyroptosis. These findings indicate that let-7a-5p is a sensitive initiator for toxic autophagy in A549 lung cancer cells and is an appealing target for lung cancer therapy.

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Section: Discussionmentioning

confidence: 96%

Crosstalk between let-7a-5p and BCL-xL in the Initiation of Toxic Autophagy in Lung Cancer

Duan

Tian

et al. 2019

Molecular Therapy - Oncolytics

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“…The CTV produces selective cancer destruction through cytolysis (promoted by viral replication) and by the multiple mechanisms in which mda-7/IL-24 can eliminate cancer cells. These include: Selective direct killing of cancer cells of diverse origin by inducing apoptosis and/or toxic autophagy; destroying localized tumors and distant metastatic tumor cells through “bystander” activity as a secreted cytokine; promoting tumor cell killing through immune-based mechanisms as a potent immune-modulating agent; suppressing tumor growth by inhibiting tumor angiogenesis; and synergizing with radiation, chemotherapy, immunotherapy, and antibody-based therapies that promote cancer cell death [ 7 , 8 , 13 , 15 , 56 , 72 ]. These properties make the CTV a potentially useful reagent for viral-based therapy of cancer [ 58 , 59 , 60 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

Theranostic Tripartite Cancer Terminator Virus for Cancer Therapy and Imaging

Bhoopathi

Pradhan

Maji

et al. 2021

Cancers

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Combining cancer-selective viral replication and simultaneous production of a therapeutic cytokine, with potent “bystander” anti-tumor activity, are hallmarks of the cancer terminator virus (CTV). To expand on these attributes, we designed a next generation CTV that additionally enables simultaneous non-invasive imaging of tumors targeted for eradication. A unique tripartite CTV “theranostic” adenovirus (TCTV) has now been created that employs three distinct promoters to target virus replication, cytokine production and imaging capabilities uniquely in cancer cells. Conditional replication of the TCTV is regulated by a cancer-selective (truncated PEG-3) promoter, the therapeutic component, MDA-7/IL-24, is under a ubiquitous (CMV) promoter, and finally the imaging capabilities are synchronized through another cancer selective (truncated tCCN1) promoter. Using in vitro studies and clinically relevant in vivo models of breast and prostate cancer, we demonstrate that incorporating a reporter gene for imaging does not compromise the exceptional therapeutic efficacy of our previously reported bipartite CTV. This TCTV permits targeted treatment of tumors while monitoring tumor regression, with potential to simultaneously detect metastasis due to the cancer-selective activity of reporter gene expression. This “theranostic” virus provides a new genetic tool for distinguishing and treating localized and metastatic cancers.

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“…Apoptosis, a mechanism of programmed cell death, is vital to maintaining cellular homeostasis and exerts its protective function by promoting the clearance of defective cells. In cancer, vulnerabilities in either extrinsic or intrinsic apoptotic pathways help tumor cells evade induction of apoptosis, in many cases contributing to the resistance to therapeutic interventions [ 97 , 98 ]. Histone modifications serve a well-established role in modulating apoptosis.…”

Section: Role Of Kdm4a In Genomic Instabilitymentioning

confidence: 99%

Mechanistic insights into KDM4A driven genomic instability

Young

Dere

2021

Biochemical Society Transactions

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Alterations in global epigenetic signatures on chromatin are well established to contribute to tumor initiation and progression. Chromatin methylation status modulates several key cellular processes that maintain the integrity of the genome. KDM4A, a demethylase that belongs to the Fe-II dependent dioxygenase family that uses α-ketoglutarate and molecular oxygen as cofactors, is overexpressed in several cancers and is associated with an overall poor prognosis. KDM4A demethylates lysine 9 (H3K9me2/3) and lysine 36 (H3K36me3) methyl marks on histone H3. Given the complexity that exists with these marks on chromatin and their effects on transcription and proliferation, it naturally follows that demethylation serves an equally important role in these cellular processes. In this review, we highlight the role of KDM4A in transcriptional modulation, either dependent or independent of its enzymatic activity, arising from the amplification of this demethylase in cancer. KDM4A modulates re-replication of distinct genomic loci, activates cell cycle inducers, and represses proteins involved in checkpoint control giving rise to proliferative damage, mitotic disturbances and chromosomal breaks, ultimately resulting in genomic instability. In parallel, emerging evidence of non-nuclear substrates of epigenetic modulators emphasize the need to investigate the role of KDM4A in regulating non-nuclear substrates and evaluate their contribution to genomic instability in this context. The existence of promising KDM-specific inhibitors makes these demethylases an attractive target for therapeutic intervention in cancers.

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Recent insights into apoptosis and toxic autophagy: The roles of MDA-7/IL-24, a multidimensional anti-cancer therapeutic

Cited by 60 publications

References 214 publications

Crosstalk between let-7a-5p and BCL-xL in the Initiation of Toxic Autophagy in Lung Cancer

Crosstalk between let-7a-5p and BCL-xL in the Initiation of Toxic Autophagy in Lung Cancer

Theranostic Tripartite Cancer Terminator Virus for Cancer Therapy and Imaging

Mechanistic insights into KDM4A driven genomic instability

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