How Chronic Inhibition of Apoptosis Promotes Cancer Formation (READ SUMMARY BELOW)

Elephants have 4 quadrillion cells, meaning 4 quadrillion opportunities to develop just ONE cancerous cell. Despite this, they have significantly lower cancer incidence than humans. They also have x20 more copies of p53, the most commonly mutated gene found in human cancer.
SUMMARY OF THEORY
-DNA damage provides signals that should initiate apoptosis in precancerous cells. However, chronic exposure to signals that prevent apoptosis (such as BCAA, Hyper-Insulinemia, IGF-1) block the activation of apoptosis, which enables precancerous cells continued cell division that may promote oncogenesis. However, sensitizing precancerous cells to sense DNA damage to initiate apoptosis may modestly reduce cancer incidence.
DNA damage sensitizing/pro-Apoptosis
-Hypoxic exercising, calorie-restriction, metformin, IGF receptor mutations provide signals that allow for robust cellular damage surveillance systems to initiate apoptosis upon exposure of cellular damage. Aspirin may prime cancerous cells for apoptosis by enhancing p53 mediated DNA repair.
Anti-Apoptosis
-BCAA, chronic hyperinsulinemia, growth hormones provide signals that integrate into downstream pathways that regulate apoptosis. For example, constitutive exposure to BCAA and hyperinsulinemia block the pro-apoptosis signals responding from DNA damage, thus enabling precancerous cells the opportunity for continued cell division and accumulation of DNA damage because the pro-apoptosis signals are obstructed by pro-growth signals from constitutive exposure to BCAA, hyperinsulinemia, IGF-1. This may modestly increase the rate that precancerous cells develop further mutations that result in malignancy.
NOTES
-Increased apoptosis results in increased cell turnover, which can be an energetically wasteful process and perhaps explains why evolution did not select for further robust tumor suppression.
-There’s a lot of evidence showing we’ve evolved remarkably efficient systems designed to repair and prevent DNA damage. Therefore, although carcinogens absolutely play a role in developing cancer, we’ve evolved natural cancer prevention systems that are remarkably efficient at prevent mutagenesis and cancer development. However, this is only true if we have robust p53 and Apoptosis activation and my explain why the most common mutation in cancer cells is p53, because disrupted p53 and apoptosis provides a foundation for uncontrolled mutagenesis and accumulation of mutations. Stabilizing p53 and promoting robust apoptosis systems will not prevent all cancers, but may modestly reduce cancer incidence. Nicotine products are filled with carcinogens that are highly mutagenic, however nicotine also inhibit important tumor suppressors involved in mediating the DNA damage response and immunosurveillance.
-It’s important to distinguish direct vs indirect increases in p53 activity. For example, cigarette smoke induces cellular stress, which indirectly result in up-regulated p53. This is dangerous due to collateral cellular damage. However, EGCG directly stabilizes p53, without any collateral cellular damage. p53 plays a central role in integrating cellular stress towards the regulation of apoptosis. The goal would be to directly stabilize tumor suppressor proteins without the normally prerequisite collateral damage signals needed to upregulate p53. (Aspirin, diallyl disulfide, sulphurophane, apigenin, melatonin?).
-Insulin activates mTOR, which upregulate pro-survival/antiapoptosis signals that inhibit apoptosis. There are several mechanisms, such as insulins activation of mTOR, which upregulates mitochondrial hexokinase2 activity which potently inhibits Bax, which is the primary downstream activator of apoptosis through release of cytochrome C. Also, IGF has many potent pro growth/anti apoptosis signals that also attenuate apoptosis signaling. Consistent prolonged time-intervals where apoptosis is inhibited in cells, coupled with exposure to carcinogens is the perfect environment to promote gradual mutagenesis and eventual tumor formation.
-Cellular Differentiation, Epigenetics play a mysterious role in cancer formation (along with the immune system!). The purpose of this video was to inspire students who are pursuing research