Impacts of autophagy-inducing ingredient of areca nut on tumor cells

Ching Yu Yen, Wei Fan Chiang, Shyun Yeu Liu, Chung Chih Lin, Kuo An Liao, Che Yi Lin, Wan Fang Hsieh, Yon Chi Cheng, Kai Cheng Hsu, Pin Yen Lin, Tai Chi Chen, I. Ling Lee, Mei Huei Lin, Young Chau Liu

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7 Citations (Scopus)

Abstract

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 longterm 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.

Original languageEnglish
Article numbere0128011
JournalPLoS One
Volume10
Issue number5
DOIs
Publication statusPublished - May 1 2015

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Yen, C. Y., Chiang, W. F., Liu, S. Y., Lin, C. C., Liao, K. A., Lin, C. Y., Hsieh, W. F., Cheng, Y. C., Hsu, K. C., Lin, P. Y., Chen, T. C., Lee, I. L., Lin, M. H., & Liu, Y. C. (2015). Impacts of autophagy-inducing ingredient of areca nut on tumor cells. PLoS One, 10(5), [e0128011]. https://doi.org/10.1371/journal.pone.0128011