16 Jul Study Probes Hormonal Pathway in Skin That Influences Melanoma Risk
MedicalResearch.com Interview with:
John D’Orazio, M.D., Ph.D.
Drury Pediatric Research Endowed Chair
Associate Professor, Univ. KY College of Medicine
Pediatric Hematology-Oncology
The Markey Cancer Center
Lexington, KY 40536-0096
Medical Research: What is the background for this study?
Dr. D’Orazio: Malignant melanoma is the deadliest of skin cancers, and it’s incidence has increased enormously over the last several decades. In the 1930’s only one in every fifteen hundred Americans would get melanoma in his/her lifetime. Now it’s one in fifty or sixty. Plus, it often affects young adults in the prime of their lives. Altogether, nearly 10,000 Americans die of melanoma every year. However, risk is not equally shared. Fair-skinned people who tend to burn rather than tan from sun exposure have a much higher risk than dark skinned people. On the surface, it would appear that the amount of melanin in the skin would be the only determinant of melanoma risk but the truth is more complex. Our lab has been interested in a particular hormonal pathway in the skin that directly influences melanoma risk. When UV radiation (sunlight) hits the skin, it causes damage to the cells of the skin. Cells respond to this damage to protect themselves against further injury. One way in which they do this is by turning on a hormone called melanocyte stimulating hormone, abbreviated “MSH”. Made by keratinocytes, the most abundant cells in the epidermis, MSH is directly responsible for ramping up melanin production by melanocytes, the cells that make the pigment in the skin that gives us a tan. This pigment called melanin acts as natural sunscreen and blocks UV radiation from penetrating into the skin. This is very important because people who can tan are in a much safer state the next time they get sun exposure. Because they have more melanin in the skin, the UV won’t cause as much damage. The key is to realize that UV causes mutations in melanocytes, and with enough damage to the DNA, melanocytes can turn cancerous and become melanomas. People who have the melanoma-prone, “can’t tan” skin type often have problems in this MSH hormonal pathway. Specifically, they have inherited problems with the receptor on melanocytes that binds to MSH and makes the cells make more pigment. This protein, called the melanocortin 1 receptor (or “MC1R”), is the way that melanocytes sense that the skin has been injured and needs more melanin. If the MC1R won’t signal, then melanocytes just sit there and can’t be induced to make more melanin pigment. Surely this is a major reason why people with MC1R signaling defects are at high risk of melanomas.
Medical Research: What are the main findings of this report?
Dr. D’Orazio: Our findings build on this observation. We and others have realized that besides stimulating melanocytes to make more pigment, the MSH-MC1R hormonal signaling axis also allows melanocytes to be better able to deal with UV damage to DNA. Using a unique and genetically-defined mouse model, we showed that MC1R defects result in delayed clearance of UV DNA damage in the skin. We also found that MC1R signaling was able to accelerate repair of UV DNA damage in human melanocytes. The reason why this is important is that the longer UV damage persists, the more likely it will cause actual mutations in melanocytes.
Therefore, individuals who have inherited a problem with MC1R have a multi-pronged problem with UV radiation.
- First, they don’t make enough melanin pigment (so they have less natural “sunblock” in the skin and more UV light can get through to the sensitive layers of the epidermis where melanocytes reside).
- Second, they have a sub-optimal way of dealing with DNA damage caused by UV, so over time their melanocytes will accumulate more mutations from UV than others who can repair the damage better because of a “good” MSH-MC1R signaling axis.
We uncovered a critical molecular link that explains how MC1R signaling impacts DNA repair pathways in melanocytes. Specifically, we confirmed that MC1R signaling increases cAMP second messenger in the cytoplasm, which in turn activates cAMP-dependent protein kinase (also called PKA). The new finding is that PKA then adds a phosphate group to a critical cellular protein called ATR (“ataxia and rad3-related”), known to be recruited after cellular injury. ATR is classically thought of as a global damage-response protein. It is a serine/threonine kinase which classically phosphorylates Chk1 protein to cause cells to stop proliferating, allowing them to survey and repair DNA damage before replication can proceed (minimizing mutation risk). Our findings highlight a new role for ATR. Once phosphorylated by PKA (downstream of MC1R signaling), ATR associates with a protein called XPA, the rate-limiting factor in the nucleotide excision repair pathway, which is a major way cells rid themselves of UV-induced DNA damage.
Medical Research: Were any of the findings unexpected?
Dr. D’Orazio: Yes. PKA-mediated phosphorylation of ATR activates ATR in a unique way. Instead of causing a cell cycle arrest, phosphorylation of the Serine 435 residue of ATR promotes recruitment of the nucleotide excision repair pathway to sites of UV-induced DNA damage. In this way, melanocytes can efficiently rid themselves of UV damage that might otherwise cause permanent mutations and malignant degeneration.
Medical Research: What should clinicians and patients take away from your report?
Dr. D’Orazio: Our work really deals with melanoma prevention. By understanding how melanocytes protect themselves against UV damage, we hope to be able to develop new ways of “rescuing” these pathways in people who have inherited problems with the MC1R and would otherwise be UV-sensitive and melanoma-prone.
We now know how MC1R signaling protects melanocytes against mutations and therefore against turning into melanoma. There are at least two important translational implications from these findings:
1. It is possible that inherited mutations in ATR (specifically at Ser435) might increase lifetime melanoma risk (as MC1R mutations are known to do).
2. It might be possible to pharmacologically modify melanoma risk. We hope to use this newly-found knowledge in developing new and effective therapies to help people lower their melanoma risk and make tanning safer.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. D’Orazio: This work is quite basic in nature at this stage. Part of what we did in the paper was to see how some very common MC1R mutations found in actual humans respond to UV damage. We confirmed that certain MC1R mutations (the exact same ones that are associated with tendency to burn rather than tan after sun exposure and the exact same ones that predict up to a four-fold increased lifetime risk of melanoma) cannot activate the ATR pathway we discovered and so accumulate mutations at a much higher level than normal. This explains why melanomas run in families and how MC1R mutations (very common in fair-skinned, UV-sensitive people) predispose to melanoma. Most people know their UV tendencies and about how much UV they can handle without getting burned, but one implication of our work is that if someone knew that he or she carried an MC1R (or ATR) mutation that blunted their ability to fix UV damage in the skin, they should certainly practice vigorous sun safety and stay out of tanning beds as well.
Our current research builds on this novel observation, further delineating how melanocytes protect themselves and the skin in general against the dangers of UV radiation.
Citation:
Last Updated on July 16, 2014 by Marie Benz MD FAAD