Chakravarthy, R., Clemens, M. J., Pirianov, G., Perdios, N., Mudan, S., Cartwright, J. E., Elia, A. (2013) Role of the eIF4E binding protein 4E-BP1 in regulation of the sensitivity of human pancreatic cancer cells to TRAIL and celastrol-induced apoptosis. BIOLOGY OF THE CELL, 105 (9). pp. 414-429. ISSN 0248-4900

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Abstract

Background Information. Tumour cells can be induced to undergo apoptosis after treatment with the tumour necrosis factor -related death-inducing ligand (TRAIL). Although human pancreatic cancer cells show varying degrees of response they can be sensitised to the pro-apoptotic effects of TRAIL in the presence of celastrol, a natural compound extracted from the plant Tripterygium wilfordii Hook F. One important aspect of the cellular response to TRAIL is the control of protein synthesis, a key regulator of which is the eukaryotic initiation factor 4E-binding protein, 4E-BP1. Results. We examined the effects of celastrol and TRAIL in several pancreatic cancer cell lines. In cells that are normally resistant to TRAIL, synergistic effects of TRAIL plus celastrol on commitment to apoptosis and inhibition of protein synthesis were observed. These were associated with a strong up-regulation and dephosphorylation of 4E-BP1. The enhancement of 4E-BP1 expression, which correlated with a threefold increase in the level of the 4E-BP1 transcript, was blocked by inhibitors of reactive oxygen species and the JNK protein kinase. When the expression of 4E-BP1 was reduced by an inducible micro-RNA, TRAIL-mediated apoptosis was inhibited. Conclusion. These results suggest that 4E-BP1 plays a critical role in the mechanism by which TRAIL and celastrol together cause apoptotic cell death in human pancreatic tumour cells.

Item Type:	Article
All Authors:	Chakravarthy, R., Clemens, M. J., Pirianov, G., Perdios, N., Mudan, S., Cartwright, J. E., Elia, A.
Additional Information:	ISI Document Delivery No.: 209RW Times Cited: 0 Cited Reference Count: 57 Chakravarthy, Reka Clemens, Michael J. Pirianov, Grisha Perdios, Nectarios Mudan, Satvinder Cartwright, Judith E. Elia, Androulla Ralph Bates Pancreatic Cancer Research Fund This work was supported by grants from the Ralph Bates Pancreatic Cancer Research Fund. Wiley-blackwell Hoboken
Uncontrolled Keywords:	anti-cancer protein synthesis therapeutic triterpene tumour necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) initiation-factor 4e n-terminal kinase kappa-b translation initiation tumor-cells signaling pathways eif-4e expression down-regulation up-regulation inhibition
Research teams:	Clinical Units > Academic Surgery
Depositing User:	Barry Jenkins
Date Deposited:	07 Oct 2013 15:39
Last Modified:	07 Oct 2013 15:39
URI:	http://publications.icr.ac.uk/id/eprint/12745

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