Curcumin sensitizes kidney cancer cells to TRAIL-induced apoptosis via ROS-mediated link between Endoplasmic Reticulum stress and MAPK activation


Year:

Session type:

Theme:

Ismael Obaidi1,Michael Higgins2,Tara McMorrow3
1University of Babylon,2Bayer Ltd,3UCD center for Toxicology/ University College Dublin

Abstract

Background

The Holy Grail in cancer therapy is to get an agent that is able to eradicate cancerous tumors without harming normal tissues. Much research has focused on fulfilling this goal. The use of TRAIL in cancer therapy has been considered as an attractive option to the scientific community to tumor cells with minimal toxicity on normal cells. However, the development of resistance against TRAIL by many tumor cells limits TRAIL’s therapeutic applications in the clinical settings. Curcumin induces apoptosis via activation of several signalling pathways causing caspase dependent cell death. Furthermore, curcumin has been shown to induce ROS production based on several in vitro and in vivo studies.

Method

In this study, kidney cancerous ACHN cell were exposed to curcumin, TRAIL, and the combination of both. Several techniques were used including resazurin and crystal violet-based cytotoxicity assays, caspases assays, flow cytometry for ROS detection and cell surface receptors expression, and qRT-PCR and western blot for detection of target genes expression.

Results

Curcumin, by itself or in a combination with TRAIL, did not only cause an inhibition of cellular metabolism, but also permanently induced caspase-dependent apoptotic cell death. Targeting ACHN cells with curcumin or curcumin/ TRAIL combination induced ROS production. High ROS level caused an increase of ER stress, upregulation of death receptors, and dysregulation of MAPK pathways. Curcumin, alone or in a combination with TRAIL, was shown to induce the expression of stress associated protein kinases, JNK and P38, while suppressed the expression of the survival kinase ERK. The pretreatment of cells with NAC, abolished the effect of curcumin or curcumin/ TRAIL combination on CHOP and MAPK protein expression.

Conclusion

Curcumin was shown to sensitise ACHN cells to TRAIL induced apoptosis. Therefore, it could be a cheaper and immensely-effective agent to be used to reverse TRAIL resistance in the clinical studies.