Abstract
Disruption of adenylyl cyclase type 5 (AC5) knockout (KO) is a novel model for longevity. Because malignancy is a major cause of death and reduced lifespan in mice, the goal of this investigation was to examine the role of AC5KO in protecting against cancer. There have been numerous discoveries in genetically engineered mice over the past several decades, but few have been translated to the bedside. One major reason is that it is difficult to alter a gene in patients, but rather a pharmacological approach is more appropriate. The current investigation employs a parallel construction to examine the extent to which inhibiting AC5, either in a genetic knockout (KO) or by a specific pharmacological inhibitor protects against cancer. This study is unique, not only because a combined genetic and pharmacological approach is rare, but also there are no prior studies on the extent to which AC5 affects cancer. We found that AC5KO delayed age-related tumor incidence significantly, as well as protecting against mammary tumor development in AC5KO × MMTV-HER-2 neu mice, and B16F10 melanoma tumor growth, which can explain why AC5KO is a model of longevity. In addition, a Food and Drug Administration approved antiviral agent, adenine 9-β-D-arabinofuranoside (Vidarabine or AraAde), which specifically inhibits AC5, reduces LP07 lung and B16F10 melanoma tumor growth in syngeneic mice. Thus, inhibition of AC5 is a previously unreported mechanism for prevention of cancers associated with aging and that can be targeted by an available pharmacologic inhibitor, with potential consequent extension of lifespan.
Highlights
A significant impediment to improving cancer therapy is the relatively small numbers of new tumor-inhibitory mechanisms for which effective therapies can be developed for translation to patients
Our retrospective analysis demonstrated that AC5KO exhibited a significant delay in age-related tumor incidence (P < 0.01; Fig. 1A), which can help explain the prolonged longevity in this model (Yan et al, 2007)
Our results show that pharmacological adenylyl cyclase type 5 (AC5) inhibition protects against tumor growth and against both tumor cell and host mechanisms facilitating tumor growth in syngeneic mouse models and in murine tumor cell lines; for example, LP07 lung adenocarcinoma (Urtreger et al, 2001; Peluffo et al, 2004), LLC1, B16F10 melanoma cells (Fig. S2)
Summary
A significant impediment to improving cancer therapy is the relatively small numbers of new tumor-inhibitory mechanisms for which effective therapies can be developed for translation to patients. One potential source for discovering novel molecular mechanisms that protect against malignancy is a longevity model, because a major cause of premature death in mice can be attributed to this disease process. One such model, which we discovered and described, is the knockout of adenylyl cyclase type 5 (AC5). Because mice do not generally die of heart disease, but do die of malignancy, the first goal of this investigation was to determine whether knockout of AC5 (AC5KO) would protect against spontaneous tumors over the mouse lifespan and to determine its role in protection against induced tumors This investigation identifies for the first time that knockout of this AC isoform protects against cancer. The results could not have been predicted, as no prior study has examined the role of AC5 in mediating tumor growth
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