Researchers demonstrate involvement of N-cadherin, c-MYC, and SIRT1.
Investigators report that reducing levels of the cell-surface protein N-cadherin on cancer cells blocks the ability of pancreatic cancer cells to migrate to other tissue and metastasize. The team showed in mouse models that reducing N-cadherin expression delays tumor progression and prolongs survival by 25%.
N-cadherin has previously been implicated in tumor growth. The new research, by researchers at Thomas Jefferson University Center for Translational Medicine, implicates the protein as a key regulatory of multiple signaling pathways crucial to cancer progression.
“Our survival results are very exciting because a drug, known as ADH-1, that specifically targets N-cadherin is already in clinical trial for melanoma,” Glenn Radice, Ph.D., lead investigator on the study, remarks. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. “The next step is to test this N-cadherin-function blocking drug or a similar compound in the pancreatic cancer mouse model to see if it can prolong survival.” The Thomas Jefferson team reports its findings in Nature Oncogene.
In a separate paper in PNAS, German researchers claim that a positive feedback loop that results in overproduction of the regulatory protein c-MYC plays a key role in tumor growth. Investigators at the Ludwig-Maximilians-Universität München have found that high levels of c-MYC, which are present in most tumor cells, activate SIRT1, an enzyme that inhibits both senescence and apoptosis, and that the two proteins are involved in a positive feedback loop.
Normally, multiple mechanisms regulate expression of c-MYC, and the gene is activated only when triggered by specific growth-promoting signals, explain Heiko Hermeking, M.D., at LMU’s Institute of Pathology, and colleagues. Even if this mechanism is disabled, a second regulatory system ensures that increased concentrations of c-MYC cause premature cell senescence and induce apoptosis. However, in tumor cells such regulatory mechanisms no longer function, and research has indicated that in some cancers c-MYC itself is responsible for knocking them out.
The team’s latest research indicates that c-MYC acts to enhance SIRT1 function and also blocks a natural SIRT1 inhibitor from functioning. SIRT1 then itself further potentiates the effects of increased c-MYC by reducing the rate of c-MYC degradation, and so the feedback loop is propagated.
“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,” comments professor Hermeking “In particular, combinations of drugs that interact with different components of the loop could provide a new route to effective therapies of these malignancies.”