Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer.
Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of β-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer.
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.
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RK
Bikkavilli
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.
S
S
Avasarala
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.
M
M
Van Scoyk
Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
J
J
Arcaroli
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.
C
C
Brzezinski
Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
W
W
Zhang
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
M G
MG
Edwards
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.
M K K
MK
Rathinam
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.
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T
Zhou
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.
J
J
Tauler
Department of Hematology and Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
S
S
Borowicz
University of Arizona Cancer Center, Tucson, AZ, USA.
Y A
YA
Lussier
Center for functional genomics, University of Albany, Rensselaer, NY, USA.
B A
BA
Parr
Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
C D
CD
Cool
Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine Research Building, University of Illinois at Chicago, Chicago, IL, USA.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
R A
RA
Winn
D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D044786:S-Phase Kinase-Associated Proteins / Q000502:physiology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; C092778:WNT7A protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D016285:Iloprost