Ablation of galectin-3 induces p27 KIP1-dependent premature senescence without oncogenic stress

S. J. Kim, H. W. Lee, H. Gu Kang, S. H. La, Il Ju Choi, J. Y. Ro, R. S. Bresalier, J. Song, K. H. Chun

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19 Citations (Scopus)

Abstract

Premature senescence induced by oncogenic stimuli or tumor suppressor activation plays opposing roles in tumorigenesis. Here, we propose that galectin-3, a β-galactoside-binding lectin, regulates premature senescence without oncogenic stress. We detected premature senescence, decreased Skp2, and increased p27 KIP1 expression in galectin-3 knockout MEFs and galectin-3-depleted gastric cancer cells. Interestingly, galectin-3 depletion did not affect other senescence inducers such as p14 ARF, p16 INK4A, and p21 WAF1/CIP1, suggesting that galectin-3-regulated senescence is p27 KIP1 dependent. We demonstrate that galectin-3 depletion decreases retinoblastoma protein (Rb) phosphorylation (Ser780, Ser807/811), cyclin D1 and CDK4 expression, and E2F1 transcriptional activation. Galectin-3 directly interacts with the cyclin D1/CDK4 complex and promotes hyperphosphorylation of Rb. It also blocks the inhibition of E2F1 transcription, thereby increasing the expression of Skp2 and reducing the stability of p27 KIP1 to promote the proliferation of gastric cancer cells. Xenograft mice with galectin-3-depleted gastric cancer cells display tumor growth retardation that is reversed by Skp2 overexpression. Increased expression of galectin-3 is also associated with the advanced TNM (tumor, lymph node, metastasis) system, clinicopathological stage, and lymph node metastases. The probability of survival was significantly decreased in gastric cancer patients with galectin-3 high p27 KIP1-low cells. Taken together, our results show that galectin-3 may accelerate gastric tumorigenesis by inhibiting premature senescence.

Original languageEnglish
Pages (from-to)1769-1779
Number of pages11
JournalCell Death and Differentiation
Volume21
Issue number11
DOIs
Publication statusPublished - 2014 Nov 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Kim, S. J., Lee, H. W., Gu Kang, H., La, S. H., Choi, I. J., Ro, J. Y., Bresalier, R. S., Song, J., & Chun, K. H. (2014). Ablation of galectin-3 induces p27 KIP1-dependent premature senescence without oncogenic stress. Cell Death and Differentiation, 21(11), 1769-1779. https://doi.org/10.1038/cdd.2014.88