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p53 Function

The p53 field has been growing at a rapid pace with more than 2,500 articles published since 1989. However, it’s still poorly understood as an important tool in clinical application. Briefly, the p53 gene is a transcriptional factor, a potential master regulator with a broad range of biological functions that include primarily blocking cell cycle progression to induce apoptosis, senescence, DNA metabolism, and angiogenesis.^4,5 To activate the apoptosis mechanism, p53 transcriptionally regulates other apoptotic genes such as Bax while simultaneously suppressing the BcL2 antagonist.⁶ It is a potent anti-apoptotic oncogene that when activated blocks Bax in promoting apoptosis.⁷ Both reduced Bax expression and overexpressed BcL2 are associated with poor response to chemotherapy and shorter survival of cancer patients.⁸

Thus, we may better understand the role of WT p53 in the apoptosis process since low p53 gene activity or even loss of p53 has some negative effects by not being able to regulate BcL2 and Bax expression. For instance, Bax is lost in one-third of breast cancers and BcL2 is activated in 60% of breast cancers, which contribute to drug resistance and shorter survival.⁹ Both BcL2 and Bax have potential prognostic and predictive significance. Several studies have shown that high Bax expression is associated with improving survival in a number of cancers. Bax and BcL2 are evaluated in a ratio that determines the fate of cells or the level of self-destroyed cancer cells. The Bax/BcL2 ratio may be used as a predictive value for chemotherapy response and offer a better evaluation of what results can be expected.¹⁰ I have been able to observe and follow the Bax/BcL2 ratio with the blood testing we usually do with cancer patients. Thus, we can improve this ratio by using a variety of select natural compounds. Another strong inhibitor of apoptosis protein is survivin, which is highly expressed in cancer tissue, yet undetectable in healthy tissue.

Being only expressed in cancer tissue, survivin is being used as a new cancer marker, a prognostic factor, and a promising therapeutic target in chemotherapy because of the resistance of cancer cells. Survivin expression is observed in virtually all cancers, including breast and prostate cancers.^11-12 Survivin was found to inhibit three apoptotic enzymes: caspase 3, caspase 7, and caspase 9, thus protecting cells from death. Survivin may act simultaneously with the BcL2 proteins, although differently as I have frequently observed with my cancer patients. Survivin is transcriptionally repressed by wild type p53 but not by mutant p53,¹³ which again may explain the crucial role of wild type p53 in apoptosis and against cancer cell resistance during chemotherapy.

p53 Mutation

The bad news: p53 itself is the most commonly mutated gene in the human body. Mutated p53 is harbored in more than half of all cancers and appears necessary to develop many forms of cancer.¹⁴ It’s important to remember that in oncology, p53 mutation is a major obstacle to patient remission, causing cancer recurrence and decreased lifespan. p53 mutation not only blocks apoptosis but when mutated, p53 acquires additional functionality, known as gain-of-function (GOF),¹⁵ by causing change and up-regulation in gene expression that promotes tumor growth, angiogenesis, immune suppression, migration, and metastasis invasion. The p53 gene is part of a network where cross-talking regulation occurs with a number of genes such as RAS, ID4, E2F1, E-Cadherin, TGF-β, EGFR, C-Myc, and even nuclear factor kappa B (NF-κβ). It’s not surprising that p53 loss or mutant p53 enhances NF-κβ, which in turn activates other mechanisms of tumor growth that, when upregulated by mutant p53, contribute not only to chemotherapy resistance in cancer cells but additionally contribute to tumor growth and metastasis invasion.

For instance, cancer cells can break the basal membrane and undergo epithelial-mesenchymal transition (EMT) and acquire migratory properties. Mutant p53 may induce EMT by up-regulation of TGF-β responsible for bone and lung metastasis in breast cancer.¹⁷ (See Figure 1) When activated, WT p53 produces a protein that adheres to the DNA core domain of the gene to activate apoptosis; but when the protein is degraded by MDM2 (murine double minute 2), it becomes a negative regulator of the p53 gene. This mutant p53 protein is not degraded and accumulates. The more it accumulates, the more aggressive the cancer. For instance, I have often observed a high level of mutant p53 protein in all aggressive ovarian cancer cases but managed to reverse it to a wild type protein by using natural compounds that I have selected through my extensive clinical experience. Mutant protein eliminates the normal function of the WT protein by forming oligomeric complexes with WT protein through a dominant-negative effect, thus inactivating its function.

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