December 21, 2011
Positive Feedback And Tumorigenesis
A vicious circle that promotes cell proliferation
Cancer cells are essentially immortal. The acquisition of an unlimited capacity to divide — the process of immortalization - is a central event in the genesis of tumors. Normally, cells are subject to stringent mechanisms which control their proliferation. Together these ensure that pre-malignant cells are induced to enter a senescent, non-dividing state or to undergo apoptosis, i.e. commit suicide. A research team led by Professor Heiko Hermeking and Dr. Antje Menssen from LMU´s Institute of Pathology has now discovered how the regulatory protein c-MYC subverts these controls, thus facilitating the growth of tumors. High levels of c-MYC, which are present in most tumor cells, activate SIRT1, an enzyme that inhibits both senescence and apoptosis. The new results show that the two proteins actually form a positive feedback loop, in that SIRT1 also promotes the activity of c-MYC. Normal cells avoid this vicious circle because they keep the gene that codes for c-MYC turned off, unless they receive growth-promoting signals. In tumor cells, this mechanism no longer functions and the cells can proliferate unchecked. Their latest findings have implications for cancer treatment, as Menssen explains: “Our results indicate that tumor types in which c-MYC plays a crucial role, such as lymphomas and colon or breast cancers, should be especially susceptible to pharmacological inhibitors that interrupt the feedback loop. In particular, combinations of drugs that interact with different components of the loop could provide a new route to effective therapies of these malignancies.” (PNAS 19.-23.12)
The hunch turned out to be correct, since the team, which included molecular biologists from Aachen University and the Karolinska Institute in Stockholm, was able to show that c-MYC actually enhances SIRT1 function in a number of different ways. First, it activates NAMPT (nicotinamide phosphoribosyltransferase), which is responsible for the synthesis of a molecule required for the action of SIRT1. Secondly, c-MYC represses an inhibitor of SIRT1, so releasing a further brake on its function. Finally, SIRT1 itself potentiates these effects by reducing the rate of degradation of c-MYC. The end result is a positive feedback loop which drives the continuous accumulation of both SIRT1 and c-MYC in the cell.
The c-MYC protein is synthesized in large amounts in most tumors. Furthermore, in certain cancers, such as lymphomas and cancers of the colon and the breast, c-MYC is known to play a causative role in the origin of the primary tumor. In these cases, mutations in the c-MYC gene itself, or in genes that regulate its expression, result in constant production of the c-MYC protein. The new findings are thus of particular relevance for the development of new treatment options for these types of cancer, since one would expect them to be highly sensitive to direct inhibition of SIRT1 or NAMPT. Interestingly, several studies in recent years have revealed that levels of NAMPT are also increased in many tumors. Indeed, a chemical inhibitor of NAMPT is already undergoing clinical trials. “Our study strongly suggests that the feedback loop initiated by excess c-MYC drives the overproduction of NAMPT. A combination of drugs that would allow us to inhibit the actions of both SIRT1 and NAMPT might therefore have a synergistic effect and could open up new therapeutic possibilities,” Menssen points out.
In addition, the new findings raise questions regarding the allegedly positive effect of a daily glass of red wine on lifespan. The putative health benefits of this regime have been attributed in part to the activation of SIRT1 by the compound resveratrol, which is found in red wine. Indeed, commercial development of pharmacological SIRT1 activators such as resveratrol is already underway — in the hope that they will slow the aging process and block the development of obesity and diabetes. In this context, Hermeking advises caution: “In the light of our results, these agents should only be used after further extensive study.”
The project was supported by a Habilitation Fellowship (funded by the Exzellence Initiative at LMU) to Dr. Antje Menssen, and by the Deutsche Krebshilfe e.V. and the Max-Planck-Society.
On the Net: