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

R. K. Bikkavilli, S. Avasarala, M. Van Scoyk, J. Arcaroli, C. Brzezinski, W. Zhang, M. G. Edwards, M. K.K. Rathinam, Tong Zhou, J. Tauler, S. Borowicz, Yves A Lussier, B. A. Parr, C. D. Cool, R. A. Winn

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25 Scopus citations

Abstract

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 p16INK4a and p19ARF 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.Oncogene advance online publication, 2 March 2015; doi:10.1038/onc.2015.2.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Mar 2 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    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. (Accepted/In press). Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer. Oncogene. https://doi.org/10.1038/onc.2015.2