Abstract
p16Ink4a is a potent cell cycle inhibitor engaged to support cell cycle arrest during cellular senescence. However, in tumors carrying mutations in key downstream effectors, p16Ink4a is highly expressed but fails to block cell proliferation. p16Ink4a-overexpressing tumor cells are highly aggressive and no targeted interventions are available. To study the effect of specific therapies, we generated murine sarcomas by overexpressing RAS oncogene and disrupting p53 activity. We observed that p16Ink4a-overxpressing murine sarcoma cells were resistant to ABT-263 and ABT-737, anti-cancer small molecules previously shown to eliminate p16Ink4a+ senescent cells. We then generated sarcoma cells carrying a suicide and reporter gene, called 3MR, under the regulation of the full p16Ink4a promoter. Activation of the suicide efficiently killed p16Ink4a-overxpressing sarcoma cells in vitro and in vivo.These data suggest that suicide gene therapy could represent an important therapeutic approach for the treatment of highly aggressive p16Ink4a+ cancers.
Highlights
CDK4/6, p16Ink4a activity is not sufficient to arrest cell cycle progression [6]
We observe that p16Ink4aoverexpressing sarcoma cells are resistant to small molecules shown to be toxic against p16Ink4a +-senescent cells, but are sensitive to a novel suicide gene therapy regulated by the full p16Ink4a promoter
Combination of RAS overexpression with p53 inactivation, obtained through the use of a Genetic Suppressor Element (GSE) which interferes with p53 tetramerization [9], was sufficient to overcome both cycle arrest and activation of SA-βgal (Figure 1A-1C)
Summary
P16Ink4a is the principal member of the Ink family of Cyclin-Dependent Kinase (CDK) inhibitors, which arrests cell cycle progression by inhibiting the S phase [1]. Loss-of-function mutations affecting p16Ink4a are a common mark of various human tumors, and considered an essential step towards tumor progression [5]. In the presence of mutations affecting RB or CDK4/6, p16Ink4a activity is not sufficient to arrest cell cycle progression [6]. P16Ink4a overexpression has been observed at the invasive front of endometrial, colorectal and basal cell carcinoma and correlated with high aggressiveness [7]. Under these conditions targeting p16Ink4a-overexpressing cells could be a potent anti-cancer intervention. We observe that p16Ink4aoverexpressing sarcoma cells are resistant to small molecules shown to be toxic against p16Ink4a +-senescent cells, but are sensitive to a novel suicide gene therapy regulated by the full p16Ink4a promoter
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