Abstract
Elevated expression of placenta-specific protein 1 (PLAC1) is associated with the increased proliferation and invasiveness of a variety of human cancers, including ovarian cancer. Recent studies have shown that the tumor suppressor p53 directly suppresses PLAC1 transcription. However, mutations in p53 lead to the loss of PLAC1 transcriptional suppression. Small molecules that structurally convert mutant p53 proteins to wild-type conformations are emerging. Our objective was to determine whether the restoration of the wild-type function of mutated p53 could rescue PLAC1 transcriptional suppression in tumors harboring certain TP53 mutations. Ovarian cancer cells OVCAR3 and ES-2, both harboring TP53 missense mutations, were treated with the p53 reactivator HO-3867. Treatment with HO-3867 successfully rescued PLAC1 transcriptional suppression. In addition, cell proliferation was inhibited and cell death through apoptosis was increased in both cell lines. We conclude that the use of HO-3867 as an adjuvant to conventional therapeutics in ovarian cancers harboring TP53 missense mutations could improve patient outcomes. Validation of this conclusion must, however, come from an appropriately designed clinical trial.
Highlights
OVCAR3 cells contain the frequent p53 gain-of-function mutant R248Q and were derived from a patient presenting with high-grade serous ovarian cancer, the most common and deadly type
ES-2 ovarian cancer cells are a model of clear-cell ovarian carcinoma and harbor a different p53 binding domain mutation, S241F
Is a DNA contact mutant overrepresented in ovarian cancers [43]
Summary
In the two decades since PLAC1 was initially reported, many papers have demonstrated its co-opted expression in numerous human cancers [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. Regardless, it is well established that PLAC1 is an oncogene in addition to being a fetal–placental gene
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