Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells

Wang, Feng-Ming; Galson, Deborah L.; Roodman, G. David; Ouyang, Hongjiao

doi:10.1016/j.exphem.2011.06.007

« Previous Next »Experimental Hematology
Volume 39, Issue 10 , Pages 999-1006, October 2011

Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells

Feng-Ming Wang
- Department of Medicine/Hematology-Oncology and the Center for Bone Biology of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, Pa., USA
- The State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
Deborah L. Galson
- Department of Medicine/Hematology-Oncology and the Center for Bone Biology of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, Pa., USA
- Veterans Administration Pittsburgh Healthcare System, Pittsburgh, Pa., USA
G. David Roodman
- Department of Medicine/Hematology-Oncology and the Center for Bone Biology of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, Pa., USA
- Veterans Administration Pittsburgh Healthcare System, Pittsburgh, Pa., USA
Hongjiao Ouyang
- Department of Medicine/Hematology-Oncology and the Center for Bone Biology of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, Pa., USA
- Department of Comprehensive Care, Restorative Dentistry, and Endodontics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pa., USA
- Offprint requests to: Hongjiao Ouyang, Ph.D., The VA Pittsburgh Healthcare System, R&D151-U, 2W-143, University Drive C, Pittsburgh, PA 15240.

Received 31 March 2011; received in revised form 27 May 2011; accepted 21 June 2011. published online 04 July 2011.

Objective

Resveratrol, trans-3, 4′, 5,-trihydroxystilbene, suppresses multiple myeloma (MM). The endoplasmic reticulum (ER) stress response component inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) axis is essential for MM pathogenesis. We investigated the molecular action of resveratrol on IRE1α/XBP1 axis in human MM cells.

Materials and Methods

Human MM cell lines ANBL-6, OPM2, and MM.1S were utilized to determine the molecular signaling events following treatment with resveratrol. The stimulation of IRE1α/XBP1 axis was analyzed by Western blot and reverse transcription polymerase chain reaction. The effect of resveratrol on the transcriptional activity of spliced XBP1 was assessed by luciferase assays. Chromatin immunoprecipitation was performed to determine the effects of resveratrol on the DNA binding activity of XBP1 in MM cells.

Results

Resveratrol activated IRE1α as evidenced by XBP1 messenger RNA splicing and phosphorylation of both IRE1α and its downstream kinase c-Jun N-terminal kinase in MM cells. These responses were associated with resveratrol-induced cytotoxicity of MM cells. Resveratrol selectively suppressed the transcriptional activity of XBP1s while it stimulated gene expression of the molecules that are regulated by the non-IRE1/XBP1 axis of the ER stress response. Luciferase assays indicated that resveratrol suppressed the transcriptional activity of XBP1s through sirtuin 1, a downstream molecular target of resveratrol. Chromatin immunoprecipitation studies revealed that resveratrol decreased the DNA binding capacity of XBP1 and increased the enrichment of sirtuin 1 at the XBP1 binding region in the XBP1 promoter.

Conclusions

Resveratrol exerts its chemotherapeutic effect on human MM cells through mechanisms involving the impairment of the pro-survival XBP1 signaling and the activation of pro-apoptotic ER stress response.