Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2002 Apr 15;16(8):984-93.
doi: 10.1101/gad.973602.

p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas

Bhuvanesh Singh  1 , Pabbathi G Reddy, Andy Goberdhan, Christine Walsh, Su Dao, Ivan Ngai, Ting Chao Chou, Pornchai O-Charoenrat, Arnold J Levine, Pulivarthi H Rao, Archontoula Stoffel
Affiliations

p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas

Bhuvanesh Singh et al. Genes Dev. .

Abstract

Interactions between the p53 and PI3K/AKT pathways play a significant role in the determination of cell death/survival. In benign cells these pathways are interrelated through the transcriptional regulation of PTEN by p53, which is required for p53-mediated apoptosis. PTEN exerts its effects by decreasing the phosphorylated AKT fraction, thereby diminishing prosurvival activities. However, the link between these pathways in cancer is not known. In this study, PIK3CA, encoding the p110alpha catalytic subunit of PI3K, is identified as an oncogene involved in upper aerodigestive tract (UADT) carcinomas. Simultaneous abnormalities in both pathways are rare in primary tumors, suggesting that amplification of PIK3CA and mutation of p53 are mutually exclusive events and either event is able to promote a malignant phenotype. Moreover, the negative effect of p53 induction on cell survival involves the transcriptional inhibition of PIK3CA that is independent of PTEN activity, as PTEN is not expressed in the primary tumors. Conversely, constitutive activation of PIK3CA results in resistance to p53-related apoptosis in PTEN deficient cells. Thus, p53 regulates cell survival by inhibiting the PI3K/AKT prosurvival signal independent of PTEN in epithelial tumors. This inhibition is required for p53-mediated apoptosis in malignant cells.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Identification of two amplification peaks at 3q26.3. FISH analysis with BAC genomic clones, of five head and neck squamous-cell carcinoma cell lines containing 3q26–27 amplification, identified two independent amplification peaks within BAC clones 202B22 and 386M7.
Figure 2
Figure 2
(A) Correlation between PIK3CA amplification, expression, and function. A high degree of correlation was detected between PIK3CA copy number by FISH, RNA expression (semiquantitative RT–PCR), and protein expression (Western blot analysis) in head and neck (left) and lung (right) carcinoma cell lines. Elevated PI3K 110α expression corresponded with phosphorylated AKT levels. PTEN protein was not detected in head and neck carcinoma derived cell lines. (B) Impact of PI3K inhibition. The impact of PI3K inhibition by LY294002 on cell viability was measured by the MTT assay. A dose-dependent sensitivity was detected in all cell lines, but was highest in cell lines containing high-level PIK3CA amplification. (C) Reduction of phosphorylated AKT protein levels in MDA886 resulted from PI3K inhibition by LY294002.
Figure 3
Figure 3
Transformation of 3T3 cells by PIK3CA. (A) myrPIK3CA- or asPIK3CA-transfected 3T3 cells were subjected to cell viability measurement with the MTT assay (±1 standard deviation) showing significantly enhanced growth in myrPIK3CA-transfected cells and a growth reduction in cells transfected with asPIK3CA. (B) Preservation of growth in serum deficient media was seen in myrPIK3CA-transfected cells. (C) Transfection of myrPIK3CA results in changes associated with dedifferentiation, including loss of spindle cell morphology and contact growth inhibition, compared with the null vector transfected (D) cells.
Figure 4
Figure 4
Effects of p53 induction on PI3K-p110α and PTEN expression. Northern (A) and Western (B) blot analyses of EB1 cells induction of p53 by 100μM zinc resulted in transcriptional activation of p21 and MDM2. A fourfold induction in PTEN expression and a sixfold down-regulation of PIK3CA expression was detected by both Northern and Western blot analyses. A decrease in phosphorylated AKT levels resulted from the p53-related PTEN induction and PIK3CA inhibition. (C,D,E) Results from analysis of synergism between p53 induction and PI3K inhibition. Significant synergism was demonstrated with p53 induction by zinc and PI3K inhibition with LY294002 in EB1 cells.
Figure 5
Figure 5
(A) Western blot analysis of cell lines exposed to 200J of ultraviolet irradiation (UV). In A549, with wild-type p53 and intact PTEN protein expression, UV exposure resulted in increased p53 protein expression and related increase in PTEN and decrease in PI3K p110α and phosphorylated AKT levels. In cell line MDA886, containing wild-type p53 and no PTEN protein expression, UV exposure resulted in a decrease in PI3K p110α and phosphorylated AKT protein levels. In cell line H157, containing mutated p53 and PTEN, UV irradiation had no effects on PI3K p110α, or AKT protein levels. (B,C) Synergism analysis between p53 induction and PI3K inhibition in cell line A549 showing cell viability (B) and isobologram (C). Synergism was identified at all dose levels. (D,E) Synergism analysis in cell line MDA 886. Synergism was detected in a dose dependent manner and to a greater extent than in cell line A549. (F,G) Transfection of myrPIK3CA into MDA886 results in resistance to p53-related apoptosis, as shown in growth curve F and abrogates p53-related decrease in phosphorylated AKT compared to null vector detected by Western blotting (G). Transfection of asPIK3CA into MDA886 cells resulted in rapid cell death and increased sensitivity to UV irradiation (F).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alper O, De Santis ML, Stromberg K, Hacker NF, Cho-Chung YS, Salomon DS. Anti-sense suppression of epidermal growth factor receptor expression alters cellular proliferation, cell-adhesion, and tumorigenicity in ovarian cancer cells. Int J Cancer. 2000;88:566–574. - PubMed
    1. Bhuyan DK, Reddy PG, Bhuyan KC. Growth factor receptor gene and protein expressions in the human lens. Mech Aging Dev. 2000;113:205–218. - PubMed
    1. Bjorkqvist AM, Husgafvel-Pursiainen K, Anttila S, Karjalainen A, Tammilehto L, Mattson K, Vainio H, Knuutila S. DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma. Genes Chromosomes Cancer. 1998;22:79–82. - PubMed
    1. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci. 1999;96:4240–4245. - PMC - PubMed
    1. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. - PubMed

MeSH terms

LinkOut - more resources