Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer

• Published in: Oncogene 2015-10, Vol.34 (42), p.5317-5328
• Main Authors: Bikkavilli, R K, Avasarala, S, Van Scoyk, M, Arcaroli, J, Brzezinski, C, Zhang, W, Edwards, M G, Rathinam, M K K, Zhou, T, Tauler, J, Borowicz, S, Lussier, Y A, Parr, B A, Cool, C D, Winn, R A
• Format: Article
• Language: English
• Subjects: 13/31; 45/91; 631/67/1612/1350; 64/60; 96/95; Animals; Apoptosis; beta Catenin - physiology; Cell Biology; Cell Line, Tumor; Cellular Senescence - drug effects; Genetic aspects; Human Genetics; Humans; Iloprost - pharmacology; Internal Medicine; Lung cancer; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Oncology; Original; original-article; Physiological aspects; S-Phase Kinase-Associated Proteins - physiology; Signal Transduction; Tumor Suppressor Proteins - physiology; Wnt proteins; Wnt Proteins - physiology
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.2

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.