Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling

Chao Hsiang Chang, Chao Ying Lee, Chi Cheng Lu, Fuu Jen Tsai, Yuan Man Hsu, Je Wei Tsao, Yu Ning Juan, Hong Yi Chiu, Jai Sing Yang, Ching Chiung Wang

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Resveratrol is known to be an effective chemopreventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-Triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-Activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-Triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy-and pro-Apoptosis-related signals in resveratrol-Treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells.

Original languageEnglish
Pages (from-to)873-882
Number of pages10
JournalInternational Journal of Oncology
Volume50
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

Fingerprint

AMP-Activated Protein Kinases
Mouth Neoplasms
Autophagy
Cisplatin
Apoptosis
resveratrol
Acridine Orange
Caspase Inhibitors
Caspase 9
Phytochemicals
DNA Fragmentation
Vacuoles
Phosphatidylinositol 3-Kinases
Drug Resistance
Caspase 3
Organelles
Mouth
Neoplasms
Phosphorylation
Staining and Labeling

Keywords

  • AMP-Activated protein kinase
  • Apoptosis
  • Autophagic Death
  • Cisplatin-resistant oral cancer cell
  • Resveratrol

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells : A key role of AMPK and Akt/mTOR signaling. / Chang, Chao Hsiang; Lee, Chao Ying; Lu, Chi Cheng; Tsai, Fuu Jen; Hsu, Yuan Man; Tsao, Je Wei; Juan, Yu Ning; Chiu, Hong Yi; Yang, Jai Sing; Wang, Ching Chiung.

In: International Journal of Oncology, Vol. 50, No. 3, 01.03.2017, p. 873-882.

Research output: Contribution to journalArticle

Chang, Chao Hsiang ; Lee, Chao Ying ; Lu, Chi Cheng ; Tsai, Fuu Jen ; Hsu, Yuan Man ; Tsao, Je Wei ; Juan, Yu Ning ; Chiu, Hong Yi ; Yang, Jai Sing ; Wang, Ching Chiung. / Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells : A key role of AMPK and Akt/mTOR signaling. In: International Journal of Oncology. 2017 ; Vol. 50, No. 3. pp. 873-882.
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AU - Tsai, Fuu Jen

AU - Hsu, Yuan Man

AU - Tsao, Je Wei

AU - Juan, Yu Ning

AU - Chiu, Hong Yi

AU - Yang, Jai Sing

AU - Wang, Ching Chiung

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AB - Resveratrol is known to be an effective chemopreventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-Triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-Activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-Triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy-and pro-Apoptosis-related signals in resveratrol-Treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells.

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