Abstract
The TP53 tumor suppressor is mutated in ~75% of pancreatic cancers. The mutant TP53 protein in pancreatic ductal adenocarcinomas (PDAC) promotes tumor growth and metastasis. Attempts have been made to develop molecules that restore at least some of the properties of wild-type (WT) TP53. APR-246 is one such molecule, and it is referred to as a mutant TP53 reactivator. To understand the potential of APR-246 to sensitize PDAC cells to chemotherapy, we introduced a vector encoding WT-TP53 into two PDAC cell lines, one lacking the expression of TP53 (PANC-28) and one with a gain-of-function (GOF) mutant TP53 (MIA-PaCa-2). APR-246 increased drug sensitivity in the cells containing either a WT or mutant TP53 protein with GOF activity, but not in cells that lacked TP53. The introduction of WT-T53 into PANC-28 cells increased their sensitivity to the TP53 reactivator, chemotherapeutic drugs, and signal transduction inhibitors. The addition of WT-TP53 to PDAC cells with GOF TP53 also increased their sensitivity to the drugs and therapeutics, indicating that APR-246 could function in cells with WT-TP53 and GOF TP53. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function through the reactivation of TP53.
Highlights
Pancreatic cancer accounts for the second highest number of cancer deaths [1,2]
We have examined the effects of APR-246 on pancreatic ductal adenocarcinomas (PDAC) cells which have GOF TP53 proteins or lack TP53 (TP53 null), and the same cell lines with introduced WT-TP53
The effects of the mutant TP53 APR-246 reactivator APR-246 on clonogenicity were examined in two pancreatic cell lines: MIA-PaCa-2, which contains GOF mutant TP53 on both alleles [23,24], and PANC-28, which does not produce detectable TP53 [25,26]
Summary
Pancreatic cancer accounts for the second highest number of cancer deaths [1,2]. The. An approach to inhibit the effects of mutant GOF TP53 is the isolation of small molecule TP53 activators (reactivators) that interact with the mutant TP53 protein and restore some of its tumor suppressor activity. An example of such reactivators is APR-246 [11–15]. Both KRAS alleles have codon 12 mutations (GGT → GAT) an2d.1.GCOelFl LTiPne5s3amnduCtautlitounrse (R248W) [23,24]. PDAC cells were infected with the respective retroviral supernatants in the presence of 10 μg/mL polybrene from Sigma-Aldrich (Saint Louis, MO, USA) for 2 h, and the medium was removed, and fresh selection medium was added, to generate pools of stable transfectants. The PDAC cell lines were infected with the either the retrovirus encoding WT-TP53 or the pLXSN empty vector, as described previously [27,28]
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