Abstract
Mutant p53(s) are widely considered as oncogenes and promote several gain-of-function oncogenic activities. p53 mutations correlate with higher rates of metastasis and poor survival; therefore, it is paramount to inhibit mutant p53 protein either directly or indirectly. Although some compounds have been developed, none of them have achieved a desirable level of specificity. Some of these compounds only targeted specific mutations. In search of less-toxic compounds, we tested plant-derived compounds on mutant p53 triple-negative breast cancer cell lines. Here, we show that the compounds tested reduced the protein levels of one of the more frequent oncogenic p53 mutants (R249S; hot spot mutation), and its important targets that promote invasion and metastasis, including GMPS and IMPDH1. All compounds tested perturbed the invasion potential of the breast cancer cell line. These compounds downregulated several nucleotide metabolism genes (NMGs) which are essential for cell cycle progression. We observed S-phase arrest correlating to reduced cell proliferation and increased replication stress. Moreover, we also show a reduction of key ETS transcription family members including ETS2, ETS1, ETV1, and ETV4, which are involved in invasion and metastasis. We propose that these compounds may inhibit invasion by interfering with multiple pathways. Our findings exemplify that these tested compounds could inhibit invasion and cell growth in TNBC in a nucleotide-dependent manner.
Highlights
50% of all human cancers harbor several different gain-of-function mutations [1]
We have previously shown that the reduction of nucleotide metabolism genes (NMGs) correlates with a reduced nucleotide pool
The dose-dependent reduction of mtp53, ETS2, and nucleotide metabolism gene transcripts can be seen after the treatment with EGCG (A), Genistein (B), Silymarin (C), and 3,3’-Diino (D)
Summary
50% of all human cancers harbor several different gain-of-function mutations [1]. Few drugs have shown to be effective in restoring wild-type p53 functions of mp in cell line and xenograft models [4,5] None of these compounds progressed into clinical trials due to specificity and toxicity issues. We tested specific plant-derived natural compounds to assess their potential to inhibit cell growth arrest and invasion in mtp cancer cell lines The effect of these compounds on mtp protein levels is not known. In our in vitro study, these compounds reduced the invasive potential of BT-549, which was derived from a TNBC patient This is the first study of its kind showing the potential of plant-derived compounds to downregulate mtp, its binding partner ETS2, and their direct transcriptional targets in a TNBC cell line
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