Preprint Article Version 1 This version is not peer-reviewed

Lambertianic Acid Sensitizes Non-Small Cell Lung Cancers to TRAIL-Induced Apoptosis Via Inhibition of XIAP/NF-kB and Activation of Caspases and Death Receptor 4

Version 1 : Received: 18 April 2018 / Approved: 18 April 2018 / Online: 18 April 2018 (15:25:10 CEST)

A peer-reviewed article of this Preprint also exists.

Ahn, D.S.; Lee, H.J.; Hwang, J.; Han, H.; Kim, B.; Shim, B.; Kim, S.-H. Lambertianic Acid Sensitizes Non-Small Cell Lung Cancers to TRAIL-Induced Apoptosis via Inhibition of XIAP/NF-κB and Activation of Caspases and Death Receptor 4. Int. J. Mol. Sci. 2018, 19, 1476. Ahn, D.S.; Lee, H.J.; Hwang, J.; Han, H.; Kim, B.; Shim, B.; Kim, S.-H. Lambertianic Acid Sensitizes Non-Small Cell Lung Cancers to TRAIL-Induced Apoptosis via Inhibition of XIAP/NF-κB and Activation of Caspases and Death Receptor 4. Int. J. Mol. Sci. 2018, 19, 1476.

Journal reference: Int. J. Mol. Sci. 2018, 19, 1476
DOI: 10.3390/ijms19051476

Abstract

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population and cleaved poly (ADP-ribose) polymerase (PARP) and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) and enhanced the activation of pro-apoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-B), inhibitory protein of kB family (p-IB) and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-B. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-B in TRAIL resistant NSCLCs.

Subject Areas

Non-small cell lung cancer; Lambertianic acid; Apoptosis; TRAIL; XIAP; NF-B

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