Oncotarget

Research Papers:

Jolkinolide B induces apoptosis of colorectal carcinoma through ROS-ER stress-Ca2+-mitochondria dependent pathway

Jing Zhang, Yang Wang, Ye Zhou and Qing-Yu He _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:91223-91237. https://doi.org/10.18632/oncotarget.20077

Metrics: PDF 1030 views  |   HTML 1340 views  |   ?  


Abstract

Jing Zhang1,*, Yang Wang1,*, Ye Zhou1 and Qing-Yu He1

1Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China

*These authors contributed equally to this work

Correspondence to:

Qing-Yu He, email: tqyhe@jnu.edu.cn

Keywords: jolkinolide B, iTRAQ proteomics, ROS, ER stress, Ca2+

Received: May 13, 2017     Accepted: July 26, 2017     Published: August 09, 2017

ABSTRACT

Colorectal carcinoma (CRC) remains one of the leading causes of death in cancer-related diseases. In this study, we aimed to investigate the anticancer effect of Jolkinolide B (JB), a bioactive diterpenoid component isolated from the dried roots of Euphorbia fischeriana Steud, on CRC cells and its underlying mechanisms. We found that JB suppressed the cell viability and colony formation of CRC cells, HT29 and SW620. Annexin V/PI assay revealed that JB induced apoptosis in CRC cells, which was further confirmed by the increased expression of cleaved-caspase3 and cleaved-PARP. iTRAQ-based quantitative proteomics was performed to identify JB-regulated proteins in CRC cells. Gene Ontology (GO) analysis revealed that these JB-regulated proteins were mainly involved in ER stress response, which was evidenced by the expression of ER stress marker proteins, HSP90, Bip and PDI. Moreover, we found that JB provoked the generation of reactive oxygen species (ROS), and that inhibition of the ROS generation with N-acetyl L-cysteine could reverse the JB-induced apoptosis. Confocal microscopy and flow cytometry showed that JB treatment enhanced intracellular and mitochondrial Ca2+ level and JC-1 assay revealed a loss of mitochondrial membrane potential in CRC after JB treatment. The mitochondrial Ca2+ uptake and depolarization can be blocked by Ruthenium Red (RuRed), an inhibitor of mitochondrial Ca2+ uniporter. Taken together, we demonstrated that JB exerts its anticancer effect by ER stress-Ca2+-mitochondria signaling, suggesting the promising chemotherapeutic potential of JB for the treatment of CRC.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 20077