Here we show that pemetrexed-treated mesothelioma cells undergo accelerated senescence. This is characterized by the secretion of proinflammatory and mitogenic cytokines, reminiscent of an SASP (senescence-associated secretory phenotype). Conditioned media from senescent MPM (malignant pleural mesothelioma) cells trigger the emergence of EMT (epithelial-to-mesenchymal)- like, clonogenic and chemoresistant cell subpopulations, expressing high levels of ALDH (aldehyde dehydrogenase) activity (ALDH bright cells). We show by fluorescence-activated cell sorting of purified ALDH bright and ALDH low cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDH bright cells exist within primary MPM specimens and enrichment for ALDH bright cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RAS v12 expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RAS v12 expression. We identify STAT3 activation as a crucial event downstream to SASP signaling. In fact, small hairpin RNA-mediated ablation of STAT3 deeply attenuates the induction of EMT genes and the increase of ALDH bright cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.
|Titolo:||SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells|
|Parole Chiave:||chemoresistance; EMT; mesothelioma; SASP; Aldehyde Dehydrogenase; Animals; Cell Count; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic; Culture Media, Conditioned; Cytokines; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genes, ras; Glutamates; Guanine; Humans; Male; Mesoderm; Mesothelioma; Mice; Mitogens; Pemetrexed; RNA, Small Interfering; STAT3 Transcription Factor; Signal Transduction; Cellular Senescence; Drug Resistance, Neoplasm; Phenotype|
|Settore Scientifico Disciplinare:||Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica|
|Data di pubblicazione:||2012|
|Digital Object Identifier (DOI):||10.1038/onc.2011.485|
|Appare nelle tipologie:||01 - Articolo su periodico|