Abstract:
:Tumour suppressor p53, a master transcriptional regulator determines cell fate through preferential activation/repression of a myriad of genes during stress. Till date, activation and preferential binding of p53 on different promoters was reported to be influenced by the nature, strength and duration of stress which mediates its post translational modifications. Cisplatin, a widely used cytotoxic drug represses PIK3CA promoter activity and attenuates PI3K/AKT cell survival pathway through p53 activation in sensitive cells. However, very little is understood about the overall mechanism of p53-PIK3CA interaction and influence of p53 on the transcriptional status of PIK3CA during cisplatin resistance. Here we showed that cisplatin could dynamically alter p53 occupancy between the p53 binding sequences present in PIK3CA promoter in ovarian and breast cancer cells. This altered occupancy is dictated by higher acetylation and hyper-phosphorylation at serine 15, serine 20 and serine 46 residues. Interestingly, cisplatin resistant cells when challenged with cisplatin demonstrated abolished PIK3CA promoter attenuation, low level of p53 binding, and loss of p53 serine 46 phosphorylation. A phosphorylation deficient S46A mutant failed to repress PIK3CA in p53 deficient cells. Elevated expression of Bcl2, P27 and cFLIP indicated a pro-survival state in these resistant cells. Non-invasive real time imaging using two different luciferase reporters showed that cisplatin could simultaneously induce PIK3CA attenuation and p53 activation with growth regression in sensitive tumours but not in the resistant tumours where only low level of p53 activation and sustained growth was observed. This is the first report on phosphorylation of p53 serine 46 as a modulator of p53-PIK3CA promoter interaction which influences altered binding of p53 at different consensus sequences in the same promoter in response to chemotherapeutic stress. Absence of such modulation in resistant cellular milieu influences cellular homoeostasis in platinum-resistant cells probably due to altered post translational modification of p53.
journal_name
Mol Oncoljournal_title
Molecular oncologyauthors
Thakur B,Ray Pdoi
10.1016/j.molonc.2016.06.006subject
Has Abstractpub_date
2016-10-01 00:00:00pages
1283-95issue
8eissn
1574-7891issn
1878-0261pii
S1574-7891(16)30060-6journal_volume
10pub_type
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