MTH1 expression is required for effective transformation by oncogenic HRAS
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Maria G. Giribaldi1,2, Anisleidys Munoz1, Katherine Halvorsen1,3, Asmita Patel1,4, Priyamvada Rai1,5
1Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
2University of California, San Diego, CA, USA
3OPKA-CURNA, Miami, FL, USA
4Beckman-Coulter Lifesciences, Indianapolis, IN, USA
5Sylvester Comprehensive Cancer Center, University of Miami, FL, USA
Priyamvada Rai, e-mail: [email protected]
Keywords: MTH1, oncogenic RAS, transformation, EMT, glycolysis
Received: July 22, 2014 Accepted: February 24, 2015 Published: March 19, 2015
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.
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