Long‐term stimulation of areca nut components results in increased chemoresistance through elevated autophagic activity

Yen, Ching Yu; Chiang, Wei Fan; Liu, Shyun Yeu; Cheng, Pse Chou; Lee, Sheng Yang; Hong, Wen; Lin, Pin Yen; Ma, Lin; Liu, Young Chau

doi:10.1111/jop.12102

Cited by 19 publications

(17 citation statements)

References 34 publications

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“…Although cytotoxic and autophagic effects of ANE and ANE 30‐100K were revealed, it is thought that oral tumor cells receiving sublethal concentrations of these AN ingredients might exhibit higher but cytoprotective autophagy activities against stressed conditions in AN chewers. This speculation is further verified in our recent studies that long‐term treatment of malignant cells with non‐cytotoxic concentrations of ANE or ANE 30‐100K (both ≤1.25 μg/mL) result in increased resistance against stressed conditions such as cisplatin and serum deprivation through elevated autophagic activities . Similar increased cisplatin resistance was also observed in oral carcinoma cell lines after 6‐day ANE (3 μg/mL) treatment …”

Section: Introductionsupporting

confidence: 73%

Clathrin‐mediated endocytosis is required for ANE 30‐100K‐induced autophagy

Liu

et al. 2017

J Oral Pathology Medicine

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Section: Introductionsupporting

confidence: 73%

Clathrin‐mediated endocytosis is required for ANE 30‐100K‐induced autophagy

Liu

et al. 2017

J Oral Pathology Medicine

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“…We previously showed that chronic treatment of non-cytotoxic ANE or ANE 30–100K resulted in increased chemoresistance through elevated autophagic activity in OECM-1 and Jurkat T cells [ 35 ]. Here, we further demonstrated that chronic ANE 30–100K-stimulated multiple myeloma RPMI8226, lymphoma U937, and SCC15 cells also exhibited higher viability and expressed higher LC3-II level under serum-free conditions for 24 hours than their non-stimulated parental cells ( S5A and S5B Fig, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, clarifying the pro-cancer role of autophagy in a specific type of cancer is essential for consideration of autophagy inhibition in cancer therapy. Our previous study revealed that long-term ANE and ANE 30–100K treatment could upregulate autophagy in OECM-1 and Jurkat T cells to increase their tolerance against cisplatin [ 35 ]. Here, we further demonstrate that chronic ANE 30–100K stimulation can also increase the survival of three different cancer cells under serum-limited conditions by the same mechanism.…”

Section: Discussionmentioning

confidence: 99%

Impacts of Autophagy-Inducing Ingredient of Areca Nut on Tumor Cells

et al. 2015

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Areca nut (AN) is a popular carcinogen used by about 0.6-1.2 billion people worldwide. Although AN contains apoptosis-inducing ingredients, we previously demonstrated that both AN extract (ANE) and its 30-100 kDa fraction (ANE 30-100K) predominantly induce autophagic cell death in both normal and malignant cells. In this study, we further explored the action mechanism of ANE 30-100K-induced autophagy (AIA) in Jurkat T lymphocytes and carcinoma cell lines including OECM-1 (mouth), CE81T/VGH (esophagus), SCC25 (tongue), and SCC-15 (tongue). The results showed that chemical- and small hairpin RNA (shRNA)-mediated inhibition of AMP-activated protein kinase (AMPK) resulted in the attenuation of AIA in Jurkat T but not in OECM-1 cells. Knockdown of Atg5 and Beclin 1 expressions ameliorated AIA in OECM-1/CE81T/VGH/Jurkat T and OECM-1/SCC25/SCC-15, respectively. Furthermore, ANE 30-100K could activate caspase-3 after inhibition of Beclin 1 expression in OECM-1/SCC25/SCC15 cells. Meanwhile, AMPK was demonstrated to be the upstream activator of the extracellular-regulated kinase (ERK) in Jurkat T cells, and inhibition of MEK attenuated AIA in Jurkat T/OECM-1/CE81T/VGH cells. Finally, we also found that multiple myeloma RPMI8226, lymphoma U937, and SCC15 cells survived from long-term non-cytotoxic ANE 30-100K treatment exhibited stronger resistance against serum deprivation through upregulated autophagy. Collectively, our studies indicate that Beclin-1 and Atg5 but not AMPK are commonly required for AIA, and MEK/ERK pathway is involved in AIA. Meanwhile, it is also suggested that long-term AN usage might increase the resistance of survived tumor cells against serum-limited conditions.

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“…Regarding the chemoresistance, 5-FU treatment also induces autophagic responses in multiple types of gastrointestinal cancer cells [ Figure 1 ]. [ 25 26 27 28 29 30 ] So far, the molecular mechanisms of 5-FU-induced autophagy remain poorly defined. Many studies have examined the synergistic effect of autophagy and 5-FU in colorectal cancer, hepatocellular carcinoma (HCC), pancreatic adenocarcinoma, esophageal cancer, gallbladder carcinoma (GBC), and gastric cancer [ Table 1 ]; some hold great promise and are currently being investigated within the context of phase I and phase II clinical trials [ Table 2 ].…”

Section: A Utophagy-mediated C Hemoresismentioning

confidence: 99%

Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer

Tang

Feng

Liang

et al. 2016

Chinese Medical Journal

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Objective:5-Fluorouracil (5-FU)-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice. This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system.Data Sources:All articles published in English from 1996 to date those assess the synergistic effect of autophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed. The search terms were “autophagy” and “5-FU” and (“colorectal cancer” or “hepatocellular carcinoma” or “pancreatic adenocarcinoma” or “esophageal cancer” or “gallbladder carcinoma” or “gastric cancer”).Study Selection:Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency of autophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized. The exclusion criteria for the articles were as follows: (1) new materials (e.g., nanomaterial)-induced autophagy; (2) clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers; and (3) immunogenic cell death for anticancer chemotherapy.Results:Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death. Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce. The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials.Conclusion:Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in gastrointestinal cancer.

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Long‐term stimulation of areca nut components results in increased chemoresistance through elevated autophagic activity

Abstract: Chronic stimulations of ANE or ANE 30-100 K may increase tolerance of oral cancer and leukemia T cells to anticancer drugs, as well as to glucose deprivation and hypoxia conditions, and cause an elevation of autophagy activity responsible for increased drug resistance.

Cited by 19 publications

References 34 publications

Clathrin‐mediated endocytosis is required for ANE 30‐100K‐induced autophagy

Clathrin‐mediated endocytosis is required for ANE 30‐100K‐induced autophagy

Impacts of Autophagy-Inducing Ingredient of Areca Nut on Tumor Cells

Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer

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