title: Spreading of mesothelioma cells is rapamycin-sensitive and requires continuing translation.
abstract: The interaction of cancer cells with extracellular matrix (ECM) is important in metastasization. Here we identified the molecules of the ECM expressed by sarcomatous malignant mesothelioma, and their effect on adhesion and spreading. In addition, by analyzing the relationship between translation and attachment to matrix, we found that mesothelioma cells rely on continuing translation to efficiently attach to matrix, and rapamycin inhibition affects spreading and migration of cancer cells. Specifically, we found that sarcomatous cells produce high amounts of fibronectin, able to support the spreading of mesothelioma cells. Spreading of cancer cells on fibronectin does not require de novo transcription but is sensitive to cycloheximide, an inhibitor of protein synthesis. Next, we analyzed the involvement of the mammalian target of rapamycin (mTOR) pathway, a major pathway controlling translation. Cancer cells have a constitutively active mTOR pathway; surprisingly, inhibition of mTOR complex 1 (mTORC1) by rapamycin barely affects the global rate of translation and of initiation of translation, but deeply inhibits mesothelioma spreading on ECM. The effects of rapamycin and cycloheximide on spreading were observed in several mesothelioma cell lines, although with different magnitude. Overall, data suggest that adhesion and spreading of mesothelioma cells on ECM require the translation of pre-synthesized mRNAs, and mTORC1 activity. We speculate that mTORC1 activity is required either for the translation of specific mRNAs or for the direct modulation of cytoskeletal remodeling.
authors.affiliation: Department of Environmental and Life Sciences, University of Piemonte Orientale, Viale T. Michel 11, 15121 Alessandria, Italy. elia.ranzato@unipmn.it
authors.forename: Elia
authors.initials: E
authors.lastname: Ranzato
authors.forename: Stefano
authors.initials: S
authors.lastname: Grosso
authors.forename: Mauro
authors.initials: M
authors.lastname: Patrone
authors.forename: Pier Giacomo
authors.initials: PG
authors.lastname: Betta
authors.forename: Aldo
authors.initials: A
authors.lastname: Viarengo
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes; D009362:Neoplasm Metastasis; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D016895:Culture Media, Serum-Free; D005353:Fibronectins; D046912:Multiprotein Complexes; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D014157:Transcription Factors; D003513:Cycloheximide; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus