Xanthium strumarium Fruit Extract Inhibits ATG4B and Diminishes the Proliferation and Metastatic Characteristics of Colorectal Cancer Cells

Chang, Hsueh‐Wei; Liu, Pei‐Feng; Tsai, Wei‐Lun; Hu, Wan-Hsiang; Hu, Yongfeng; Yang, Hsiu-Chen; Lin, Wei‐Yu; Weng, Jing‐Ru; Shu, Chih‐Wen

doi:10.3390/toxins11060313

Cited by 27 publications

(32 citation statements)

References 38 publications

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“…On the other hand, silencing ATG4B significantly attenuated growth, migration, and invasion of oral cancer cells, suggesting ATG4B as a potential target for oral cancer therapy. In addition, various high-throughput screening methods have identified several ATG4B inhibitors, including the clinical drug tioconazole, the Xanthium strumarium fruit extract, and the small molecule S130 [9,13,14]. These ATG4B inhibitors can suppress colorectal cancer cell growth and synergize the killing effect of cancer cells with autophagy-induction.…”

Section: Discussionmentioning

confidence: 99%

“…Afterward, the inserts were removed to allow cells to migrate for 4 h. The distance covered by moving cells from time 0 to 4 h was counted as migration distance. We used 8 µm pore inserts (Greiner Bio-One, Stroud, UK) to determine the invasion capability of cancer cells as described before [14]. Briefly, Transwell chambers were coated with 0.5% Matrigel, and silenced cells were seeded in them in 300 µL of Dulbecco's Modified Eagle's Medium (DMEM) containing 1% Fetal Bovine Serum (FBS).…”

Section: Analysis Of Cell Viability Migration and Invasionmentioning

confidence: 99%

“…ATG4B is the most active member of the ATG4 family (ATG4A, ATG4B, ATG4C, and ATG4D) in mammalian cells [10]. The oncogenic role of ATG4B in cancers has been reported previously in cell culture, tumor xenograft models, and even in clinical settings [11][12][13][14]. ATG4B overexpression is associated with cancer development in patients with colorectal cancer and chronic myeloid lymphoma (CML) [11,15].…”

Section: Introductionmentioning

confidence: 97%

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Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Liu

Chen

Cheng

et al. 2019

Cancers

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Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Cell Viability Migration and Invasionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Liu

Chen

Cheng

et al. 2019

Cancers

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“…It is interesting to note that ATG4B inhibitors were identified in natural product sources as well, such as Xanthium strumarium food extract, though the compound has not yet been purified [122].…”

Section: Atg4b Inhibitorsmentioning

confidence: 99%

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

Agrotis

Ketteler

2019

Cells

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Autophagy is an evolutionary conserved stress survival pathway that has been shown to play an important role in the initiation, progression, and metastasis of multiple cancers; however, little progress has been made to date in translation of basic research to clinical application. This is partially due to an incomplete understanding of the role of autophagy in the different stages of cancer, and also to an incomplete assessment of potential drug targets in the autophagy pathway. While drug discovery efforts are on-going to target enzymes involved in the initiation phase of the autophagosome, e.g., unc51-like autophagy activating kinase (ULK)1/2, vacuolar protein sorting 34 (Vps34), and autophagy-related (ATG)7, we propose that the cysteine protease ATG4B is a bona fide drug target for the development of anti-cancer treatments. In this review, we highlight some of the recent advances in our understanding of the role of ATG4B in autophagy and its relevance to cancer, and perform a critical evaluation of ATG4B as a druggable cancer target.

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“…Treatment for AML is currently focused on the use of cytotoxic or cytostatic drugs that theoretically target cancer cells rather than healthy body cells. Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays represent an important pool for the identification of novel drugs [16], to decrease proliferation and metastasis of cancer, when the plant extract is used either alone [17], or in combination with known chemotherapeutic drugs [18,19].…”

Section: Introductionmentioning

confidence: 99%

Annona cherimola Seed Extract Activates Extrinsic and Intrinsic Apoptotic Pathways in Leukemic Cells

Haykal

Nasr

Hodroj

et al. 2019

Toxins

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Annona cherimola Mill is a large green fruit with black seeds widely known to possess toxic properties due to the presence of Annonaceous acetogenins. The present study investigates the anti-cancer properties of an Annona cherimola Mill ethanolic seed extract on Acute Myeloid Leukemia (AML) cell lines in vitro and elucidates the underlying cellular mechanism. The anti-proliferative effects of the extract on various AML cell lines and normal mesenchymal cells (MSCs) were assessed using WST-1 viability reagent. The pro-apoptotic effect of the extract was evaluated using Annexin V/PI staining and Cell Death ELISA. The underlying mechanism was deciphered by analyzing the expression of various proteins using western blots. Treatment with an A. cherimola seed ethanolic extract promotes a dose- and time-dependent inhibition of the proliferation of various AML cell lines, but not MSCs. Positive Annexin V staining, as well as DNA fragmentation, confirm an increase in apoptotic cell death by upregulating the expression of pro-apoptotic proteins which control both intrinsic and extrinsic pathways of apoptosis. GC/MS analysis revealed the presence of phytosterols, in addition to other bioactive compounds. In conclusion, Annona cherimola Mill seed extract, previously known to possess a potent toxic activity, induces apoptosis in AML cell lines by the activation of both the extrinsic and the intrinsic pathways.

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Xanthium strumarium Fruit Extract Inhibits ATG4B and Diminishes the Proliferation and Metastatic Characteristics of Colorectal Cancer Cells

Cited by 27 publications

References 38 publications

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

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

Annona cherimola Seed Extract Activates Extrinsic and Intrinsic Apoptotic Pathways in Leukemic Cells

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