By Prof. Serge Jurasunas, MD(Hom), ND
Abstract
Research from past decades has established that the p53 tumor suppressor gene protein provides a major barrier to neoplasic transformation and tumor progression. Its role is not only associated with controlling cell cycle progression and apoptosis, involving other apoptotic genes, but is implicated in several functions, including regulation of glycolysis, promoting oxidative phosphorylation, and repressing overactive telomerase enzymes. Cancer cells first acquire selective advantages by retaining mutant forms of p53 protein that confer new oncogenic functions that upregulate several genes that accelerate tumor progression, metastasis, and chemotherapy resistance.
In this article, we also demonstrate the new role of (Wild Type) WT p53 in controlling telomerase activity since telomerase is overexpressed in most cancers, allowing cancer cells to acquire a stem-cell-like state (CSCs). These cells can continually renew and become almost immortal. Furthermore, they are responsible for cancer recurrence and chemo-resistance. New research demonstrates that mutant p53 cannot repress telomerase enzymatic activity; only WT p53 can. This underscores the critical role that WT p53 plays in cancer therapy. The idea is to establish a new ratio between p53 and telomerase that offers a better dimension and perspective to understand and treat cancer. Several natural compounds have demonstrated efficacy to reactivate p53 function and therefore to inhibit glycolysis and telomerase activity.
Introduction
Have we explored fully the possibilities, new theories, new ways, new treatments to win the battle against cancer, or at least, to have a much better result? Probably not! Today in 2020, cancer has become an epidemic, while in 2005 Andrew Von Eschenbach, director of the NCI, announced there would be an end to deaths caused by cancer by 2015. Would you have believed such a thing back then? Some doctors did believe in this prediction. In one article published in the same year, I read the following: “We are closer than ever to achieving this goal!”
Five years later, this goal continues to be only a dream. Oncology is still in a deadlock since chemotherapy and radiation have yet to bring significant improvement to cancer patient longevity over the past 30-35 years. Cancer metastasis is still responsible for 90% of cancer deaths. Besides, oncologists have absolutely no way to detect cancer recurrence risk or prevent primary tumors, thought to be contained, from metastasizing. How many times have we seen patients undergoing chemotherapy develop more metastasis?
A 2012 study published in Natural Medicine strongly suggested that chemotherapy is responsible for disease recurrence. It is supported by Dr. Laurent Schwartz, a well-known professor of oncology at Public Hospitals in Paris, who wrote a new book, Cancer: A Simple and Non Toxic Treatment. According to some of its statements, after chemotherapy loses efficacy there follows an increased risk of metastasis. This is also supported by oncologists like Dr. Dominique Belpomme, professor of oncology at Paris-Descartes University, president of the French Association for Research on Treatment Against Cancer (ARTAC), and author of an important book on cancer, Cure of Cancer and How to Prevent: A Way to Change our Approach to the Disease. He wrote the following: “Today chemotherapy offers its maximum efficacy where we cannot expect more future progress since it has reached its upper limit.Therefore, the need for new modalities and tools for cancer prevention, cancer recurrence, and treatment with less toxicity, remain the main goal in modern oncology.”1
There is an urgent need to change the cancer paradigm by searching for new theories and methods to treat cancer with more efficacy, some of which are newly emerging. These include the theories of cellular respiration and the Warburg effect as the prime cause of cancer.2 Cancer as a metabolic disease is now gaining more interest in the scientific community. More recently, research has shown that the metabolic profile observed in cancer cells includes mitochondrial dysfunction, increased consumption of glucose, increased glycolysis, and increased secretion of lactate, while oncogenes and tumor suppressors have been discovered to have an important role in cancer.
Cancer Cell Resistance
Chemotherapy may kill many cancer cells sensitive to apoptosis; but during the treatment, a small population can acquire apoptosis resistance by the up-regulation of multiple pro-survival factors such as loss of p53 gene function and activated inhibitors of apoptosis (IAPs). In one study, survivin, an IAP, increased the activity of the nuclear factor kappa-B (NF-κβ), inducing lung metastasis of human breast cancer in nude mice treated with Paclitaxel, which was inhibited with curcumin.3
A tumor represents a diverse collection of cancer cells. When cancer is detected, the million (or billions) of cells that make up the tumor have become differentiated. Some cancer cells are sensitive to chemotherapy and apoptosis, while others emerging during the late stage of the tumor development—being actuated by the loss of p53 function as undifferentiated cancer stem cells that possess the ability to self-renew—become resistant and can usually originate metastasis. This type of cancer cell harbors mutated p53 that has gained additional oncogenic function, which I will explain in depth as we continue to address the p53 gene function.
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