title: 'Reduced malignancy as a mechanism for longevity in mice with adenylyl cyclase type 5 disruption'.
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.
authors: Department of Cell Biology & Molecular Medicine and the Cardiovascular Research Institute, New Jersey Medical School, Rutgers University, The State University of New Jersey, 185 South Orange Avenue, MSB G609, Newark, NJ, 07103, USA.
authors: Mariana S
authors: MS
authors: De Lorenzo
authors: Wen
authors: W
authors: Chen
authors: Erdene
authors: E
authors: Baljinnyam
authors: María J
authors: MJ
authors: Carlini
authors: Krista
authors: K
authors: La Perle
authors: Sanford P
authors: SP
authors: Bishop
authors: Thomas E
authors: TE
authors: Wagner
authors: Arnold B
authors: AB
authors: Rabson
authors: Dorothy E
authors: DE
authors: Vatner
authors: Lydia I
authors: LI
authors: Puricelli
authors: Stephen F
authors: SF
authors: Vatner
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D008136:Longevity / Q000187:drug effects; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: AC5 inhibitor; B16F10 melanoma; LP07 lung adenocarcinoma; MMTV-HER-2 neu mice; adenylyl cyclase (AC) knockout mice; angiogenesis; tumor protection
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