ATG4B promotes colorectal cancer growth independent of autophagic flux

Liu, Pei‐Feng; Leung, Chung-Man; Chang, Yu-Hsiang; Cheng, Jin‐Shiung; Chen, Jih Jung; Weng, Chung-Jeu; Tsai, Kuo‐Wang; Hsu, Chien-Jen; Liu, Yen‐Chen; Hsu, Ping-Chi; Pan, Hung‐Wei; Shu, Chih‐Wen

doi:10.4161/auto.29556

Cited by 70 publications

(101 citation statements)

References 56 publications

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“…Based on reports of the oncogenic roles of ATG4B in patients with colorectal cancer and CML [10, 11], we confirmed a role for ATG4B in tumor growth in various human cancer cells, including human neuroblastoma H4 cells, breast cancer MCF-7 cells and prostate cancer PPC1 cells. Silencing ATG4B with three individual or pooled siRNAs against ATG4B suppressed ATG4B expression (Fig.…”

Section: Resultsmentioning

confidence: 65%

“…Elevated expression of ATG4B has been observed in colorectal cancer and CML patients [10, 11]. Knockdown of ATG4B suppresses tumor growth in vitro and in vivo [10, 11].…”

Section: Discussionmentioning

confidence: 99%

“…ATG4 knockdown or overexpression of an ATG4B catalytic mutant impairs both the deconjugation of MAP1LC3/GABARAP orthologs and autophagosome maturation, which may, in turn, block autophagosome fusion with lysosomes [6, 28, 29]. Knockdown of ATG4B increases the MAP1LC3-II levels and GFP-MAP1LC3 puncta to suppress autophagic flux in breast cancer cells [10, 12]. In accordance with previous studies, our results show that knockdown of ATG4B increased the levels of MAP1LC3-II and GFP-MAP1LC3 puncta in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…The culture medium was changed every 3 days for 2-3 weeks. The cell colonies were fixed and stained with 0.25% crystal violet at room temperature for 30 min as previously reported [10]. The stained cells were washed with PBS to remove the background, enabling observation of the colonies.…”

Section: Methodsmentioning

confidence: 99%

“…In colorectal cancer patients, ATG4B is highly expressed in tumor cells, whereas it is minimally expressed in adjacent normal cells [10]. Likewise, ATG4B and its family members are upregulated in CD34 + chronic myeloid leukemia (CML) patients, resulting in drug resistance [11].…”

Section: Introductionmentioning

confidence: 99%

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Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

Liu

Hsu

Tsai

et al. 2017

Cell Physiol Biochem

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Background/Aims: ATG4B is a cysteine protease required for autophagy, which is a cellular catabolic pathway involved in energy balance. ATG4B expression is elevated during tumor growth in certain types of cancer, suggesting that ATG4B is an attractive target for cancer therapy. However, little is known about the mechanisms through which ATG4B deprivation suppresses the growth of cancer cells. Methods: Cancer cells were transfected with either siRNA against ATG4B or an expression vector encoding wild-type ATG4B^WT or encoding catalytic mutant ATG4B^C74A to determine cell cycle progression by propidium iodide staining or by BrdU incorporation assay using flow cytometry. The GFP-MAP1LC3-II puncta and protein levels in the cells were determined by immunofluorescence and immunoblotting, respectively. Results: Knockdown of ATG4B blocked cell proliferation, particularly at the G₁-S phase transition, in various cancer cells. Moreover, knockdown of ATG4B or overexpression of the ATG4B^C74A catalytic mutant reduced both autophagic flux and ATP levels and increased AMP-activated protein kinase (AMPK) phosphorylation in the cancer cells. Nevertheless, knockdown of ATG4B had only a minor effect on AMPK activation and G₁ phase arrest in liver kinase B1 (LKB1)-deficient or AMPK-inhibited cancer cells. Conclusion: These results imply that targeting ATG4B might inhibit autophagy and trigger the LKB1-AMPK energy-sensing pathway, resulting in tumor growth suppression.

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Section: Resultsmentioning

confidence: 65%

“…Elevated expression of ATG4B has been observed in colorectal cancer and CML patients [10, 11]. Knockdown of ATG4B suppresses tumor growth in vitro and in vivo [10, 11].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

Liu

Hsu

Tsai

et al. 2017

Cell Physiol Biochem

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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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Autophagy modulation as a potential targeted cancer therapy: From drug repurposing to new drug development

Lin

Tsao

Shu

2021

The Kaohsiung J of Med Scie

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Autophagy is an evolutionarily conserved signaling pathway to deliver dysfunctional proteins or organelles into lysosomes for degradation and recycling, which is an important pathway for normal homeostasis. Autophagy dysfunction can lead to various diseases, particularly cancer. Autophagy not only plays a role in tumor suppression, but it also serves as a tumor promoter in cancer malignancy. In this review, we summarize the involvement of autophagy‐related (ATG) proteins in autophagy signaling and the role of autophagy in cancer progression. The effectiveness of US Food and Drug Administration‐approved drugs in regulating autophagic flux and suppressing cancer cells is also discussed. Moreover, since clinically available drugs do not specifically target ATG proteins, there is little doubt that their cancer suppression function is autophagy dependent. Therefore, this review also discusses several inhibitors against ATG proteins, such as ULK1/2, ATG4, and VPS34 to suppress cancer cells. Autophagy modulators can be either used alone or combined with chemotherapy or radiation therapy to enhance the efficacy of current treatments for certain types of cancer. This review summarizes current autophagy modulation used as a potential strategy for targeted cancer therapy.

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ATG4B promotes colorectal cancer growth independent of autophagic flux

Cited by 70 publications

References 56 publications

Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

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

Autophagy modulation as a potential targeted cancer therapy: From drug repurposing to new drug development

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