On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

Agrotis, Alexander; Ketteler, Robin

doi:10.3390/cells9010053

Cited by 29 publications

(25 citation statements)

References 131 publications

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“…This is consistent with evidence reported previously that the LC3-II accumulation may be associated with elevated pH or impaired protease activity in the lysosome or defective degradation of LC3-PE on autophagosomal structures the suppression of ATG4B activity [ 48 ]. This result agreed with previous studies that reported the crucial role of ATG4B in autophagosome elongation and maturation steps of autophagic regulation that involved cancer cell differentiation and proliferation [ 49 , 50 ]. Therefore, ATG4B inhibition through the combination therapeutic strategy may serve as a new cancer therapeutic strategy tool to diminish autophagic flux and enhance chemotherapeutic drugs’ anti-tumor effect.…”

Section: Resultssupporting

confidence: 93%

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

et al. 2021

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Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity.

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Section: Resultssupporting

confidence: 93%

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

et al. 2021

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“…108 Thus, the value of isoform-specific versus pan-ATG4 inhibition to target autophagy is still debated and will require additional research. 109 Similar to other autophagy targets, several ATG4B inhibitors have been reported over the past decade, but none is yet in clinical development. 110,111 Activating/enhancing autophagy.…”

Section: Autophagy In Pdac: Translational Findingsmentioning

confidence: 99%

Autophagy as a therapeutic target in pancreatic cancer

2020

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Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.

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“…After autophagosome expansion and maturation, ATG4B is reactivated to release LC3 from the membrane junction which leads to fusion of the engulfed contents and lysosomes. 36 However, ATG4B actually promotes tumor cell migration or proliferation among several cancer types, including breast cancer, 37 pancreatic ductal adenocarcinoma, 38 colorectal cancer, 39 and prostate cancer. 40 When blocked using an inhibitor or miRNA of ATG4B , tumor cell proliferation was controlled and susceptibility towards chemotherapy was enhanced due to the repressed autophagy, in this process, pro-LC3 cannot be cleaved, and the fusion of the autophagosomes with lysosomes would also be obstructed, which means that downregulation of ATG4B is helpful to cancer cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer

Wu¹,

Chen²,

Pan³

et al. 2020

CMAR

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Autophagy-related proteins (ATG) play a crucial role in autophagy. Recently, the functions of autophagy in cancer have been gathering attention. However, the prognostic value of ATGs in gastric cancer (GC) has not been explored. Methods: The Kaplan-Meier plotter (KM plotter) online database was used to examine the value of ATGs gene expression levels in overall survival (OS) prediction in GC patients with different clinical stage, differentiation, gender, HER2 status, and therapeutic strategy. In vitro experiments applied VE-822, an effective GC treatment, to assess cell migration and proliferation in gastric mucosa epithelial cells, and real-time PCR was used to measure alterations of autophagy-related gene expression. Results: High ATG3, ATG4C, ATG5, and ATG10 mRNA levels were associated with good OS, while increased ATG4B, ATG7, ATG12, ATG16L1, and TECPR1 mRNA levels related to unfavorable OS in patients with GC. ATG12 overexpression had different effects on OS due to high levels of heterogeneity. High ATG12 expression was correlated with good OS in female patients with GC and with bad OS for male patients. Additionally, the increased ATG12 expression was more likely to get a satisfactory OS in patients who underwent surgery alone but was associated with poor OS for patients treated with 5-FU adjuvant. In addition, elevated TECPR1 expression was related to favorable OS for patients with poorly differentiated type, while for patients with moderate differentiation, it was relevant to poor OS. The in vitro experiments showed that berzosertib could significantly inhibit the migration and proliferation of human gastric mucosa epithelial cells, and further real-time PCR assessment of ATG expressions partially coincided with the bioinformation analysis above. Conclusion:These results indicate that individual ATGs have unique prognostic significance interpreted using Kaplan-Meier plotter analysis and in vitro experiments, and this may help guide clinical therapeutic strategy and promote OS by individualizing therapy for GC patients.

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On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

Cited by 29 publications

References 131 publications

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

Autophagy as a therapeutic target in pancreatic cancer

Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer

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