Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer

Zx, Lin; Yang, Bin; Zhang, Zhenhua; Wang, Junfeng; Wang, Xiaojuan; Guo, Yinfeng; Huang, Weifeng; Wang, Qianqian; Cai, Guodi; Xia, Fan; Zhou, Shengning; Ma, Shuai; Nie, Yichu; Lei, Jinping; Li, Min; Liu, Peiqing; Deng, Wenbin; Liu, Yonghong; Han, Fanghai; Wang, Junjian

doi:10.1038/s41419-022-04608-z

Cited by 28 publications

(9 citation statements)

References 45 publications

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“…Limited cohort study (n = 20) shows that ATG4B protein level is elevated in tumor parts of CRC patients [ 28 ]. Emerging studies also indicate that ATG4B silencer or inhibitor reduces cell proliferation and metastatic features of cancer cells [ 26 , 27 , 29 , 36 ]. Perhaps then, ATG4B may play its role as a tumor promoter in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, phosphorylation of ATG4B at Ser 383/392 increases its protease activity, which is involved in cancer cell growth [ 25 ]. Gene silencing of ATG4B, or, inhibiting ATG4B activity diminishes cancer cell viability and sensitizes cancer cell to chemotherapeutic drugs in vitro and in vivo suggesting ATG4B might play a role as tumor promoter [ 22 , 26 – 29 ]. However, the relationship between ATG4B or phosphorylated ATG4B and clinical outcome in patients with CRC is not known.…”

Section: Introductionmentioning

confidence: 99%

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ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer

Liu

et al. 2023

Cancer Cell Int

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Background Autophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression. Phosphorylation of ATG4B is crucial for activation of its protease activity. However, little is known about the relationship of ATG4B and its phosphorylated form at Ser 383 and 392 sites (pS383/392-ATG4B), with clinical outcomes, particularly in colorectal cancer (CRC). Methods The ATG4B gene expression in CRC patients was obtained from The Cancer Genome Atlas (TCGA) database to analyze its clinical relevance. Tissue microarrays composed of 118 CRC patient specimens were used to determine the associations of ATG4B and pS383/392-ATG4B protein levels with prognosis. The biological functions of ATG4B in CRC cells were inspected with cell proliferation, mobility and spheroid culture assays. Results ATG4B gene expression was elevated in tumor tissues of CRC patients compared to that in adjacent normal tissues and high level of ATG4B expression was associated with poor survival. Similarly, protein levels of ATG4B and pS383/392-ATG4B were highly correlated with worse overall survival and disease-free survival. Stratification analysis results showed that high level of ATG4B had significantly higher risk of mortality in males and elderly patients compared to those female patients and patients 60 years or younger. In contrast, multivariate Cox’s regression analysis indicated that high level of pS383/392-ATG4B was significantly linked to unfavorable overall survival and disease-free survival of males and elderly patients, whereas, it had no correlation with female patients and patients 60 years or younger. Moreover, high level of ATG4B was positively associated with increased mortality risk in patients with advanced AJCC stages (III and IV) and lymph node invasion (N1 and N2) for both overall survival and disease-free survival. Nevertheless, high level of pS383/392-ATG4B was positively correlated with increased mortality risk in patients with early AJCC stages (I and II) and without lymph node invasion (N0). In addition, silencing ATG4B attenuated migration, invasion, and further enhanced the cytotoxic effects of chemotherapeutic drugs in two and three-dimensional cultures of CRC cells. Conclusions Our results suggest that ATG4B and pS383/392-ATG4B might be suitable biomarkers and therapeutic targets for CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer

Liu

et al. 2023

Cancer Cell Int

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“…Depletion of ATG4B also increases the sensitivity to trastuzumab in human epidermal growth factor receptor 2-positive breast cancer cells (Bortnik et al, 2016). ATG4B potential inhibitors reduce cancer cell viability and sensitize cancer cells to chemotherapeutic drugs (H. W. Chang et al, 2019;Xu et al, 2017;Zhong et al, 2022). Moreover, reconstitution of the ATG4B C74A mutant arrests cell cycle progression at the G 1 phase in glioma cells (Liu, Hsu, et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

MAP3K11 facilitates autophagy activity and is correlated with malignancy of oral squamous cell carcinoma

Liu

Chen

Ger

et al. 2022

Journal Cellular Physiology

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Autophagy-related 4B (ATG4B) is a protease required for core machinery of autophagy. Phosphorylation of ATG4B promotes autophagy and is correlated with poor outcome of cancer. However, little is known about the upstream kinases for ATG4B phosphorylation and their association with clinical outcomes of cancer patients. Through siRNA library screening, MAP3K11 was identified as a potential kinase that phosphorylates ATG4B and increases its proteolytic activity. Ablation of MAP3K11 attenuated pS383/392-ATG4B protein levels and autophagic flux in oral cancer cells. Moreover, loss of MAP3K11 inhibited oral cancer cell growth, migration/invasion, and synergized starvation-reduced cell viability. MAP3K11 knock-out cancer cells also showed growth inhibition in vivo. Furthermore, the protein level of MAP3K11 was higher in tumor tissues than that in adjacent normal tissues in patients with oral squamous cell carcinoma (OSCC), comprising 179 buccal mucosa squamous cell carcinoma (BMSCC) and 249 tongue squamous cell carcinoma (TSCC). MAP3K11 protein levels were positively correlated with ATG4B and pS383/392-ATG4B levels in patients with OSCC, particularly in TSCC. In addition, high coexpression of MAP3K11 and ATG4B was associated with poor disease-specific survival in BMSCC and TSCC, while high coexpression of MAP3K11 and pS383/392-ATG4B was associated with unfavorable disease-free survival in BMSCC and TSCC. Taken together, our results indicated that MAP3K11

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“…ATG4B has been implicated in several cancers, such as colorectal cancer (CRC) [ 9 – 11 ], gastric carcinoma [ 12 ], and breast Cancer [ 13 ]. Among them, ATG4B was validated to be highly expressed in CRC tumor tissues, and its knockdown resulted in blocking cell cycle progression and inhibition in CRC cells, typically HCT116 cell line [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery and mechanism studies of a novel ATG4B inhibitor Ebselen by drug repurposing and its anti-colorectal cancer effects in mice

et al. 2022

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Cysteine protease ATG4B, a key autophagy protein, is an attractive target for colorectal cancer therapy. However, ATG4B inhibitors with higher efficiency, safety, and clear mechanism are still limited. In this study, we discovered ATG4B inhibitors based on the FDA-approved drug library through FRET-based high-throughput screening and gel-based analysis. Among the nine hits, compound Ebselen showed the most potent ATG4B inhibitory activity (IC50 = 189 nM) and exhibited controllable selectivity and structural optimizable possibility against ATG4A and caspases. We then performed mass spectrometry assay and cysteine mutations to confirm that Ebselen could covalently bind to ATG4B at Cys74. Moreover, Cys292 and Cys361 instead of Cys74 are responsible for the redox-oligomerization and efficient activity inhibition of ATG4B. Ultimately through cell culture and mouse xenograft tumor models, we established the impact of Ebselen on autophagy and tumor suppression via ATG4B inhibition other than apoptosis. These results suggest that old drug Ebselen as an ATG4B inhibitor through oxidative modification may be repurposed as a promising anti-colorectal cancer drug.

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Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer

Cited by 28 publications

References 45 publications

ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer

ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer

MAP3K11 facilitates autophagy activity and is correlated with malignancy of oral squamous cell carcinoma

Discovery and mechanism studies of a novel ATG4B inhibitor Ebselen by drug repurposing and its anti-colorectal cancer effects in mice

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