| First Author | Venkatanarayan A | Year | 2016 |
| Journal | Cell Cycle | Volume | 15 |
| Issue | 2 | Pages | 164-71 |
| PubMed ID | 26652033 | Mgi Jnum | J:317258 |
| Mgi Id | MGI:6851575 | Doi | 10.1080/15384101.2015.1121333 |
| Citation | Venkatanarayan A, et al. (2016) Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73. Cell Cycle 15(2):164-71 |
| abstractText | TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients. (1,2) Therapeutic strategies to reactivate the p53-pathway have been challenging, (3,4) and no effective treatment exists. (5) We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and DeltaN isoforms. We recently demonstrated that deletion of either DeltaNp63 or DeltaNp73 in p53-deficient mouse tumors results in tumor regression mediated by metabolic programming. Using this strategy, we identified pramlintide, a synthetic analog of amylin, as an effective treatment for p53 deficient and mutant tumors. Here, we show the utility of using pramlintide, as a potential cancer preventive option for p53-deficient tumors in mouse models. Additionally, we found that in vivo inhibition of both DeltaNp63 and DeltaNp73 in combination accelerates tumor regression and increases survival of p53-deficient mice. We report that inhibition of both DeltaNp63 and DeltaNp73 in combination results in upregulation of 3 key metabolic regulators, IAPP, GLS2, and TIGAR resulting in an increase in apoptosis and tumor regression in DeltaNp63/DeltaNp73/p53 deficient thymic lymphomas. These data highlight the value of generating inhibitors that will simultaneously target DeltaNp63 and DeltaNp73 to treat cancer patients with alterations in p53. |
