Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin

Serous borderline ovarian tumors (SBOTs) are slow-growing, non-invasive ovarian epithelial neoplasms. SBOTs are considered to be distinct entities that give rise to invasive low-grade serous carcinomas (LGCs), which have a relatively poor prognosis and are unrelated to high-grade serous carcinomas (HGCs). The mechanisms underlying the progression of non-invasive SBOTs to invasive epithelial ovarian carcinomas are not understood. We recently established short-term cultures of SBOT cells from tumor biopsies and showed that inactivation of p53, retinoblastoma (Rb) and/or PP2A by the simian virus 40 (SV40) large (LT) and small T antigens extends the life span of the cells and endows them with the ability to invade Matrigel-coated transwells. In this study, we show that concurrent inhibition of p53 and Rb by the SV40 LT produces cells (referred to as SBOT4-LT) with increased life span and cell invasion. To distinguish the roles of p53 and Rb in the progression from SBOTs to invasive ovarian carcinomas, we performed small interfering RNA-mediated knockdown of endogenous p53 in a spontaneously immortalized SBOT cell line, SBOT3.1, which increased cell invasion. This increased invasive activity was associated with the transcriptional downregulation of E-cadherin, correlated with an increase in PIK3CA levels and the increased activation of Akt. Conversely, in invasive LGC-derived MPSC1 cells, enhancing the levels of p53 decreased cell invasion and diminished the phosphatidylinositol 3-kinase (PI3K)/Akt-mediated downregulation of E-cadherin. Inhibition of Rb also enhanced invasiveness, but did not affect the levels of PIK3CA and E-cadherin in SBOT3.1 cells, suggesting that it functions by a different pathway. To our knowledge, this study is the first to show that p53 has an important role in the progression from SBOTs to invasive carcinomas. In addition, our findings suggest that downregulation of E-cadherin by the PI3K/Akt pathway contributes to this progression.

p53 Research: The Past Thirty Years and the Next Thirty Years

Thirty years of research on the p53 family of genes has generated almost fifty thousand publications. The first of these papers detected the p53 protein associated with a viral oncogene product in transformed cells and tumors and focused the field on cancer biology. Subsequent manuscripts have shown a wide variety of functions for the p53 family of genes and their proteins. These proteins are involved in reproduction, genomic repair, fidelity and recombination, the regulation of metabolic processes, longevity, surveillance of the stability of development, the production of stem cells and changes in epigenetic marks, the development of the nervous system (p73), the immune system (p73) and skin (p63), as well as the better known roles for the family in tumor suppression. The p53 family of genes has been found in the modern day ancestors of organisms with over one billion years of evolutionary history where they play a role in germ-line fidelity over that time span. As the body plan of the vertebrates emerged with the regeneration of tissues by stem cells over a lifetime, the p53 gene and its protein were adapted to be a tumor suppressor of somatic stem and progenitor cells complementing its' past functions in the germ line. Because the p53 family of genes has played a role in germ-line fidelity and preservation of the species, even in times of stress, these genes have been under constant selection pressure to change and adapt to new situations. This has given rise to this diversity of functions all working to preserve homeostatic processes that permit growth and reproduction in a world that is constantly challenging the fidelity of information transfer at each generation. The p53 family of gene products has influenced the rates of evolutionary change, just as evolutionary changes have altered the p53 family and its functions.

The history of p53
A perfect example of the drawbacks of scientific paradigms

"Over more than 30 years of molecular biology teaching, many dogmas have crumbled: the universal nature of the genetic code, the collinearity of genes, the share of epigenetic phenomena in the regulation of transcription, the discovery of prions and the RNA regulator revolution. In his essay on the structure of scientific revolutions, Kuhn suggested that research is discontinuous and punctuated by revolutions that are linked to paradigm shifts (Kuhn, 1970). These revolutions can have a profound impact on the entire discipline—for example the Darwinian revolution—or they can influence only a specific field. The discovery of retroviruses and their ability to induce tumours, the demonstration of reverse transcription, and the identification of viral oncogene sequences led to the emergence of the ‘virus and cancer’ paradigm, which formed the basis of US President Richard Nixon's ‘war on cancer’ in 1971."

"Consciously or unconsciously, we self‐censor our grant applications to be compatible with current paradigms"

"Our scientific reductionism has also affected funding agencies and research institutions, by limiting research to clearly defined fields" "My scientific career started in a laboratory adjacent to that of Pierre May—one of the discoverers of p53—at the Cancer Research Institute in Villejuif, France. Our institute had chosen to study cancer in the context of two related virus models: SV40 and polyoma virus. It is important to put this into the historical context of 1977; the viral theory of cancer was popular and the association between viral and cellular oncogenes was only beginning to emerge. Several other DNA tumour viruses such as human papilloma virus (HPV) and Epstein–Barr virus were already strongly associated with human neoplasia. In vitro and in vivo experiments had shown that both SV40 and polyoma viruses could transform cells or induce tumours in animals. The similarities between polyoma virus and SV40 allowed us to work in parallel on these viruses, and findings in one were rapidly confirmed in the other."

Cheng 2010: Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin

Lane 2010: p53 Research: The Past Thirty Years and the Next Thirty Years

Soussi 2010: The history of p53 A perfect example of the drawbacks of scientific paradigms