We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells.
- Authors
Canino, C; Mori, F; Cambria, A; Diamantini, A; Germoni, S; Alessandrini, G; Borsellino, G; Galati, R; Battistini, L; Blandino, R; Facciolo, F; Citro, G; Strano, S; Muti, P; Blandino, G; Cioce, M
- Abstract
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 (ALDHbright cells). We show by fluorescence-activated cell sorting of purified ALDHbright and ALDHlow cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDHbright cells exist within primary MPM specimens and enrichment for ALDHbright cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RASv12 expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RASv12 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 ALDHbright cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.
- Subjects
MESOTHELIOMA; CELLULAR aging; CYTOKINES; ALDEHYDE dehydrogenase; ANTINEOPLASTIC agents; CANCER cells; LABORATORY mice; P53 antioncogene; THERAPEUTICS
- Publication
Oncogene, 2012, Vol 31, Issue 26, p3148
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2011.485