title: MTH1 expression is required for effective transformation by oncogenic HRAS.
abstract: Due to sustaining elevated reactive oxygen species (ROS), oncogenic RAS-transformed cells upregulate redox-protective genes, among them the mammalian 8-oxodGTPase, MutT Homolog 1 (MTH1). We previously showed MTH1 abrogates RAS oncogene-induced senescence (OIS) in normal cells and that its inhibition compromises the tumorigenicity of established oncogenic RAS-harboring cancer cells. Here, we investigated how pre-transformation MTH1 levels in immortalized cells influence HRASV12-induced oncogenic transformation. We find MTH1 suppression prior to HRASV12 transduction into BEAS2B immortalized epithelial cells compromised maintenance of high RASV12- and oncogenic ROS-expressing cell populations. Furthermore, pre-transformation MTH1 levels modulated the efficiency of HRASV12-mediated soft agar colony formation. Downstream transformation-associated traits such as the epithelial-mesenchymal transition (EMT) were also compromised by MTH1 inhibition. These collective effects were observed to a greater degree in cells harboring high vs. low RASV12 levels, suggesting MTH1 is required for tumor cells to accumulate RAS oncoprotein. This is significant as, a priori, one cannot ascertain whether tumor-promoting adaptations wrought by introducing oncogenic RAS into an immortalized cell are capable of overcoming pre-transformation deficiencies. Our results suggest nucleotide pool sanitization comprises an important transformation-promoting requirement that, if compromised, cannot be adequately compensated post-transformation and thus is likely to affect optimal development and progression of RAS-driven tumors.
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.|University of California, San Diego, CA, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Giribaldi
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Anisleidys
authors.initials: A
authors.lastname: Munoz
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.|OPKA-CURNA, Miami, FL, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Halvorsen
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.|Beckman-Coulter Lifesciences, Indianapolis, IN, USA.
authors.forename: Asmita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.|Sylvester Comprehensive Cancer Center, University of Miami, FL, USA.
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Rai
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D017382:Reactive Oxygen Species; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D045643:DNA Repair Enzymes
keywords: EMT; MTH1; glycolysis; oncogenic RAS; transformation