Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP.

Mohammed I Y Elmallah,Mohammed I Y Elmallah,Mohammed I Y Elmallah,Mohammed I Y Elmallah,Mohammed I Y Elmallah,Sheron Cogo,Sheron Cogo,Sheron Cogo,Sheron Cogo,Sheron Cogo,Selene Elifio-Esposito,Olivier Micheau,Olivier Micheau,Olivier Micheau,Olivier Micheau,Mohammed S Abdelfattah,Andrei A Constantinescu,Andrei A Constantinescu,Andrei A Constantinescu,Andrei A Constantinescu

doi:10.3390/cells9081760

Abstract

Resistance of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis represents the major hurdle to the clinical use of TRAIL or its derivatives. The discovery and development of lead compounds able to sensitize tumor cells to TRAIL-induced cell death is thus likely to overcome this limitation. We recently reported that marine actinomycetes’ crude extracts could restore TRAIL sensitivity of the MDA-MB-231 resistant triple negative breast cancer cell line. We demonstrate in this study, that purified secondary metabolites originating from distinct marine actinomycetes (sharkquinone (1), resistomycin (2), undecylprodigiosin (3), butylcyclopentylprodigiosin (4), elloxizanone A (5) and B (6), carboxyexfoliazone (7), and exfoliazone (8)), alone, and in a concentration-dependent manner, induce killing in both MDA-MB-231 and HCT116 cell lines. Combined with TRAIL, these compounds displayed additive to synergistic apoptotic activity in the Jurkat, HCT116 and MDA-MB-231 cell lines. Mechanistically, these secondary metabolites induced and enhanced procaspase-10, -8, -9 and -3 activation leading to an increase in PARP and lamin A/C cleavage. Apoptosis induced by these compounds was blocked by the pan-caspase inhibitor QvD, but not by a deficiency in caspase-8, FADD or TRAIL agonist receptors. Activation of the intrinsic pathway, on the other hand, is likely to explain both their ability to trigger cell death and to restore sensitivity to TRAIL, as it was evidenced that these compounds could induce the downregulation of XIAP and survivin. Our data further highlight that compounds derived from marine sources may lead to novel anti-cancer drug discovery.

Highlights

The marine environment encompasses a great microbial biodiversity
We provide evidence here that all compounds when combined to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) display pro-apoptotic enhancing activity owing, at least in part, to their ability to induce the downregulation of the anti-apoptotic proteins survivin and X-linked inhibitor of apoptosis protein (XIAP)
[58,59], compounds displaying to increase biodiversity of unexplored microorganisms that are likely to provide an interesting source of novel apoptosis induced by TRAIL [60,61,62]

Summary

Introduction

The marine environment encompasses a great microbial biodiversity. These microorganisms are able to survive in harsh environmental conditions including high salinity, temperature, and pressure [1]and are currently considered as the major producer of a great variety of pharmacologically active secondary metabolites. The marine environment encompasses a great microbial biodiversity. These microorganisms are able to survive in harsh environmental conditions including high salinity, temperature, and pressure [1]. The standard treatment of solid tumor includes surgery to remove the cancerous lump followed by chemo/radiotherapies to get rid of the residual cells. Efforts are directed towards developing lead drugs that can kill tumor cells, but spare healthy cells. This can be achieved through restoration of tumor cell sensitivity to various apoptotic signaling pathways or by targeting pro-apoptotic receptors of the tumor necrosis (TNF) superfamily such as TRAIL-R1 or TRAIL-R2 [7,8]

Methods

Results

Conclusion