normally activate this pathway. In cancer cells, however, the pathway is activated by mutation so that the cell can grow in the absence of such signals. The resulting abnormal activation of the protein kinases Akt and mTOR not only stimulates protein synthesis (see Figure 17–64), but also greatly increases both glucose uptake and the production of the acetyl CoA in the cytosol required for cell lipid synthesis, as outlined in Figure 20–26B.
The abnormal activation of the PI 3-kinase/Akt/mTOR pathway, which normally occurs early in the process of tumor progression, helps to explain the excessive rate of glycolysis that is observed in tumor cells, known as the Warburg effect, as discussed earlier (see Figure 20–12). As expected from our previous discussion, cancers can activate this pathway in many different ways. Thus, for example, a growth factor receptor can become abnormally activated, as in Figure 20–19. Also very common in cancers is the loss of the PTEN phosphatase, an enzyme that normally suppresses the PI 3-kinase/Akt/mTOR pathway by dephosphorylating the PI (3,4,5) P3 molecules that the PI 3-kinase forms (see pp. 859–861). PTEN is thus a common tumor-suppressor gene.
Of course, mutation is not the only way to overactivate the pathway: high levels of insulin in the circulation can have a similar effect. This may explain why the risk of cancer is significantly increased, by a factor of two or more, in people who are obese or have type 2 diabetes. Their insulin levels are abnormally high, driving cancer cell growth without need of mutation in the PI 3-kinase/Akt/mTOR pathway.
Mutations in the p53 Pathway Enable Cancer Cells to Survive and Proliferate Despite Stress and DNA Damage
That cancer cells must break the normal rules governing cell growth and cell division is obvious: that is part of the definition of cancer. It is not so obvious why cancer cells should also be abnormal in their response to stress and DNA damage, and yet this too is an almost universal feature. The gene that lies at the center of this response, the p53 gene, is mutated in about 50% of all cases of cancer— a higher proportion than for any other known cancer-critical gene. When we include with p53 the other genes that are closely involved in its function, we find that most cases of cancer harbor mutations in the p53 pathway. Why should this be? To answer, we must first consider the normal function of this pathway.
In contrast to Rb, most cells in the body have very little p53 protein under normal conditions: although the protein is synthesized, it is rapidly degraded. Moreover, p53 is not essential for normal development. Mice in which both copies of the gene have been deleted or inactivated typically appear normal in all respects except one—they universally develop cancer before 10 months of age. These observations suggest that p53 has a function that is required only in special circumstances. In fact, cells raise their concentration of p53 protein in response to a whole range of conditions that have only one obvious thing in common: they are, from the cell’s point of view, pathological, putting the cell in danger of death or serious injury. These conditions include DNA damage, putting the cell at risk from a faulty genome; telomere loss or shortening (see p. 1016), also dangerous to the integrity of the genome; hypoxia, depriving the cell of the oxygen it needs to keep its metabolism going; osmotic stress, causing the cell to swell or shrivel; and oxidative stress, generating dangerous levels of highly reactive free radicals.
Yet another form of stress that can activate the p53 pathway arises, it seems, when regulatory signals are so intense or uncoordinated as to drive the cell beyond its normal limits and into a danger zone where its mechanisms of control and coordination break down, as in an engine driven badly or too fast. The p53 concentration rises, for example, when Myc is overexpressed to oncogenic levels.