Redox balance and autophagy regulation in cancer progression and their therapeutic perspective

Fatima, Kaneez; Aisha, Shariqa; Hamza, Baseerat; Khan, Sameer Ullah

doi:10.1007/s12032-022-01871-0

Cited by 18 publications

(21 citation statements)

References 289 publications

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“…When mitochondria are invaded by elevated intracellular ROS, exacerbating mitochondrial damage, the mitophagy pathway is normally activated to remove damaged mitochondria to maintain the homeostasis of the intracellular environment [34][35][36] . Mitophagy is an autophagic process in which mitochondria within a cell undergo depolarization damage and excess or damaged mitochondria are selectively removed in response to external stimuli such as ROS, nutrient de ciency, and cellular senescence [37] .…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of V8 affecting mitophagy and endoplasmic reticulum stress in acute myeloid leukemia mediated by ROS and CHOP signaling

Hui

Guo

Zhu

et al. 2023

Preprint

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Acute myeloid leukemia (AML) is a disease of malignant proliferation of abnormally or poorly differentiated myeloid cells of the hematopoietic system. The clinical treatments of non-M3 AML are experiencing a lack of effective drugs. V8 is a newly synthesized derivative of the natural flavonoid wogonin, which belongs to the potential anticancer drug, and has shown significant antitumor activity in vitro and in vivo. In this study, we investigated the effects of V8 on AML cell lines and primary AML cells and the underlying mechanisms. The results showed that V8 inhibited the growth and induced the apoptosis of AML cell lines (ME-1, Kasumi-1, and U937) and primary AML cells in a concentration-dependent manner. Meanwhile, we revealed that V8-induced apoptosis was accompanied by mitochondrial injury, such as the reduction of mitochondrial membrane potential and ATP production, activation of endoplasmic reticulum stress (ERS) characterized by GRP78 and caspase-12 expression upregulation. Mechanism studies have shown that V8 induced mitochondrial injury and inhibited mitophagy via elevating the intracellular ROS level. In addition, V8 activated PERK-p-eIF2α-ATF4 and Ire1α-XBP1 pathways and induced apoptosis of AML cells via selectively activating CHOP. Correspondingly, the degree of apoptosis and expression of apoptosis-related proteins were alleviated after the elimination of cytoplasmic ROS with N-Acetyl-L-cysteine (NAC) and knocking out CHOP in the cells by transfection with CHOP shRNA, implicating that mitochondrial injury-triggered upregulation of ROS and CHOP played an important role in V8-induced apoptosis of AML cells. In primary AML cells-bearing NOD/SCID mice model and U937 cells-inoculating BALB/c nude mice xenografts transplantation tumor model, administration of V8 markedly prolonged survival time and inhibited the xenografts growth via CHOP-mediated ERS in vivo. In conclusion, our study provides a new insight into the mechanism of V8-induced apoptosis, suggesting the potential of V8 as a promising agent against AML.

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Section: Discussionmentioning

confidence: 99%

Therapeutic effect of V8 affecting mitophagy and endoplasmic reticulum stress in acute myeloid leukemia mediated by ROS and CHOP signaling

Hui

Guo

Zhu

et al. 2023

Preprint

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“…Autophagy has a variety of different roles in tumor development and progression. Autophagy can degrade waste components in cells into nutrient components necessary for cell survival, but when autophagy is overactivated, cells can also be stimulated by this "self-digesting" degradation pathway, ultimately leading to increased apoptosis (7). There are very important links between autophagy and methods causing cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy refers to the formation of autophagosomes from the double-membrane-wrapped cytoplasm where organelles and proteins are degraded within a cell, and is important for the intracellular degradation of damaged organelles (6). Autophagy pathways have been extensively explored to study and develop therapeutic anti-cancer strategies (7). Classic autophagy-related (ATG) proteins can be divided into ve categories: (i) Unc-51 like autophagy activating kinase 1 (ULK1) protein complex, (ii) Beclin-1/ phosphoinositide 3-kinase (PI3K) complex, (iii) ATG8/microtubule-associated protein 1A/1B light chain 3 (LC3) liposome binding system, (iv) ATG12-ATG5 protein binding system, and (v) ATG9 and its circulation system.…”

Section: Introductionmentioning

confidence: 99%

Targeting GABARAPL1/HIF-2a in nasopharyngeal carcinoma

Huang

Chen

et al. 2023

Preprint

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The primary gene mutations associated with nasopharyngeal carcinoma (NPC) are located within phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling pathways. These pathways have inhibitory effects on autophagy, and autophagy has become an important area of NPC research. However, the potential molecular targets related to autophagy in NPC remain to be elucidated. The current study examined levels of autophagy-related genes, including autophagy related 4B cysteine peptidase (ATG4B) and gamma aminobutyric acid (GABA) type A receptor associated protein like 1 (GABARAPL1), in nasopharyngeal carcinoma tissues and explored their potential role as novel targets for the treatment of NPC. Overexpression of GABARAPL1 was shown to decrease the level of hypoxia-inducible factor (HIF)-2α and induce apoptosis in NPC cells. Importantly, when nude mice were subcutaneously inoculated with NPC cells, overexpression of GABARAPL1 slowed tumor growth. Furthermore, the underlying mechanism by which GABARAPL1 regulated nasopharyngeal tumor growth was investigated. HIF-2α, as a substrate for autophagic degradation, may play an interesting role during NPC progression. This study highlighted novel targets that may be used to treat NPC patients in the future.

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“…Succeeding this, the γ-secretase enzyme causes S3 cleavage, thereby leading to the formation of the Notch intracellular domain (NICD), which then binds to CSL (a DNA binding domain) in the nucleus leading to activation of transcription of Notch downstream genes including Hey, c-myc, SNAI, p21, members of NF-kB family, etc., hence bringing about the cancer cell proliferation and distribution [15]. Studies have revealed that the Notch signalling results in the conversion of hypoxic stimulus within tumors into EMT and invasiveness in the following synergistic ways: First, Notch, a crucial regulator of EMT, upregulates Snail1 expression, and second, Notch enhanced hypoxia-inducible factor 1 (HIF-1), which further promotes the stability of Snail1 protein [16][17][18][19]. Earlier in the case of MMTV (Mouse mammary tumor virus-infected mice), Notch was found as an oncogene.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive analysis of Notch signalling genes in breast cancer: Expression pattern and prognostic significance

Sofi

Qayoom

Khaliq

et al. 2023

Preprint

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The most recurrent type of cancer among women is breast cancer which is an intricate disease with high intratumoral and intratumoral heterogeneity. Such variability is a key factor in the failure of current treatments and the emergence of resistance. It is crucial to develop novel therapeutic options to enhance the prognosis for breast cancer patients due to the limitations of current therapy and the unavoidable formation of acquired drug resistance (chemo and endocrine) as well as radio resistance. Poor clinical results in the treatment of breast cancer that is resistant are associated with deregulated Notch signalling within the breast tumor and its tumor microenvironment (TME). In this research, a bioinformatics approach was used to check the expression pattern, the role, as well as the prognostic and diagnostic significance of the deregulated Notch-related genes in BC patients. The study demonstrates that highly dysregulated genes (NOTCH4, CCND1, JAG1, DLL1, MAML2, and EGFR) can be used as biomarkers to identify breast cancer patients with poor prognosis and as potential targets for therapeutic intervention. The study found that 6 genes—NOTCH4, CCND1, JAG1, DLL1, MAML2, and EGFR—out of 22 tested genes showed a significant log2 fold change. Our study revealed that Luminal Breast Cancer patients display a high expression of the CCND1 gene in comparison to its expression in normal. The results of our study also depicted that the patients with elevated levels of NOTCH-related gene expression displayed better relapse-free survival with p < 0.05. Moreover, we analysed these deregulated notch genes that play an important role in various cellular and molecular processes. The study shows that these highly deregulated screened genes could be utilized as the Biomarkers that help to reveal poor prognosis and could act as targets for treating BC.

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Redox balance and autophagy regulation in cancer progression and their therapeutic perspective

Cited by 18 publications

References 289 publications

Therapeutic effect of V8 affecting mitophagy and endoplasmic reticulum stress in acute myeloid leukemia mediated by ROS and CHOP signaling

Therapeutic effect of V8 affecting mitophagy and endoplasmic reticulum stress in acute myeloid leukemia mediated by ROS and CHOP signaling

Targeting GABARAPL1/HIF-2a in nasopharyngeal carcinoma

A comprehensive analysis of Notch signalling genes in breast cancer: Expression pattern and prognostic significance

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