Mechanistic Study of Tetrahydrofuran-acetogenins In Triggering Endoplasmic Reticulum Stress Response-apotoposis in Human Nasopharyngeal Carcinoma

Shin Hun Juang, Chang Ying Chiang, Fong Pin Liang, Hsiu Hui Chan, Jai Sing Yang, Shih Hao Wang, Yu Chin Lin, Ping-Chung Kuo, Meng-Ru Shen, Tran Dinh Thang, Bui Thi Minh Nguyet, Sheng Chu Kuo, Tian-Shung Wu

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Abstract

For past three decades, numerous studies have elucidated the antiproliferative effects of acetogenins in hopes of developing a new class of clinical anticancer agents. However, clear and definitive action mechanisms of acetogenins were less clarified. In the present study, three tetrahydrofuran (THF)-containing acetogenins were found to have potent and selective antiproliferative activity against human nasopharyngeal carcinoma (NPC) cell lines and their methotrexate-resistant counterparts. The THF-containing acetogenins induced G2/M phase arrest, mitochondrial damage and apoptosis, and increased cytosolic and mitochondrial Ca2+ in NPCs. Microarray analysis of NPC-TW01 cells treated with squamostatin A, a non-adjacent bis-THF acetogenin, demonstrated an increased endoplasmic reticulum (ER)-stress response (ESR). Enhanced ESR in squamostatin A-treated cells was confirmed by real-time PCR, Western blot and shRNA gene knockdown experiments. Although our results showed that squamostatin A-induced ESR was independent of extracellular Ca2+, the presence of extracellular Ca2+ enhanced the antiproliferative effect of acetogenins. In vivo analyses demonstrated that squamostatin A showed good pharmacokinetic properties and significantly retarded NPC tumor growth in the xenograft mouse model. Conclusively, our work demonstrates that acetogenins are effective and selective inducers of the ESR that can block NPC proliferation, and illustrate a previously unappreciated antitumor mechanism of acetogenins that is effective against nasopharyngeal malignancies.

Original languageEnglish
Article number39251
JournalScientific reports
Volume6
DOIs
Publication statusPublished - 2016 Dec 21

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Acetogenins
Endoplasmic Reticulum Stress
Gene Knockdown Techniques
tetrahydrofuran
Nasopharyngeal carcinoma
G2 Phase
Microarray Analysis
Heterografts
Human Activities
Methotrexate
Cell Division
Antineoplastic Agents
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Neoplasms
Pharmacokinetics
Western Blotting
Apoptosis
Cell Line

All Science Journal Classification (ASJC) codes

  • General

Cite this

Juang, Shin Hun ; Chiang, Chang Ying ; Liang, Fong Pin ; Chan, Hsiu Hui ; Yang, Jai Sing ; Wang, Shih Hao ; Lin, Yu Chin ; Kuo, Ping-Chung ; Shen, Meng-Ru ; Thang, Tran Dinh ; Nguyet, Bui Thi Minh ; Kuo, Sheng Chu ; Wu, Tian-Shung. / Mechanistic Study of Tetrahydrofuran-acetogenins In Triggering Endoplasmic Reticulum Stress Response-apotoposis in Human Nasopharyngeal Carcinoma. In: Scientific reports. 2016 ; Vol. 6.
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abstract = "For past three decades, numerous studies have elucidated the antiproliferative effects of acetogenins in hopes of developing a new class of clinical anticancer agents. However, clear and definitive action mechanisms of acetogenins were less clarified. In the present study, three tetrahydrofuran (THF)-containing acetogenins were found to have potent and selective antiproliferative activity against human nasopharyngeal carcinoma (NPC) cell lines and their methotrexate-resistant counterparts. The THF-containing acetogenins induced G2/M phase arrest, mitochondrial damage and apoptosis, and increased cytosolic and mitochondrial Ca2+ in NPCs. Microarray analysis of NPC-TW01 cells treated with squamostatin A, a non-adjacent bis-THF acetogenin, demonstrated an increased endoplasmic reticulum (ER)-stress response (ESR). Enhanced ESR in squamostatin A-treated cells was confirmed by real-time PCR, Western blot and shRNA gene knockdown experiments. Although our results showed that squamostatin A-induced ESR was independent of extracellular Ca2+, the presence of extracellular Ca2+ enhanced the antiproliferative effect of acetogenins. In vivo analyses demonstrated that squamostatin A showed good pharmacokinetic properties and significantly retarded NPC tumor growth in the xenograft mouse model. Conclusively, our work demonstrates that acetogenins are effective and selective inducers of the ESR that can block NPC proliferation, and illustrate a previously unappreciated antitumor mechanism of acetogenins that is effective against nasopharyngeal malignancies.",
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Mechanistic Study of Tetrahydrofuran-acetogenins In Triggering Endoplasmic Reticulum Stress Response-apotoposis in Human Nasopharyngeal Carcinoma. / Juang, Shin Hun; Chiang, Chang Ying; Liang, Fong Pin; Chan, Hsiu Hui; Yang, Jai Sing; Wang, Shih Hao; Lin, Yu Chin; Kuo, Ping-Chung; Shen, Meng-Ru; Thang, Tran Dinh; Nguyet, Bui Thi Minh; Kuo, Sheng Chu; Wu, Tian-Shung.

In: Scientific reports, Vol. 6, 39251, 21.12.2016.

Research output: Contribution to journalArticle

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AU - Juang, Shin Hun

AU - Chiang, Chang Ying

AU - Liang, Fong Pin

AU - Chan, Hsiu Hui

AU - Yang, Jai Sing

AU - Wang, Shih Hao

AU - Lin, Yu Chin

AU - Kuo, Ping-Chung

AU - Shen, Meng-Ru

AU - Thang, Tran Dinh

AU - Nguyet, Bui Thi Minh

AU - Kuo, Sheng Chu

AU - Wu, Tian-Shung

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