Title: Mechanisms of tumor growth revealed through computational analysis of transcriptomes: The case of mastic oil
Authors: Panagiotis Moulos, Olga Papadodima, Aristotelis Chatziioannou, Heleni Loutrari, Charis Roussos, Fragiskos N Kolisisß
Abstract:Mastic oil (MOIL) from Pistacia lentiscus variation chia, a blend of bioactive terpenes with recognized medicinal properties, has been recently shown to exert anti-tumor growth activity through inhibition of cancer cell proliferation, survival, angiogenesis and inflammatory response. To investigate molecular mechanisms triggered by MOIL, Lewis Lung Carcinoma cells were treated with MOIL or DMSO and RNA was collected at five distinct time points (3-48h). Microarray expression profiling was performed using Illumina mouse-6 v1 beadchips, followed by computational analysis. For a number of selected genes, RT-PCR validation was performed in LLC cells as well as in three human cancer cell lines of different origin (A549, HCT116, K562). PTEN specific inhibition by a bisperovanadium compound was applied to validate its contribution to MOIL-mediated anti-tumor growth effects.
In this work we demonstrated that exposure of Lewis lung carcinomas to MOIL caused a time-dependent alteration in the expression of 925 genes. GO analysis associated expression profiles with several biological processes and functions. Among them, modifications on cell cycle/proliferation, survival and NF-ÍB cascade in conjunction with concomitant regulation of genes encoding for PTEN, E2F7, HMOX1 (up-regulation) and NOD1 (down-regulation) indicated some important mechanistic links underlying the anti-proliferative, pro-apoptotic and anti-inflammatory effects of mastic oil. The expression profiles of Hmox1, Pten and E2f7 genes were similarly altered by mastic oil in the majority of test cancer cell lines. Inhibition of PTEN partially reversed mastic oil effects on tumor cell growth, indicating a multi-target mechanism of action. Finally, k-means clustering, organized the significant gene list in eight clusters demonstrating a similar expression profile. Promoter analysis in a representative cluster revealed shared putative cis-elements suggesting a common regulatory transcription mechanism.
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