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Ablation of galectin-3 induces p27KIP1-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 
 CELL DEATH AND DIFFERENTIATION, Vol.21(11) : 1769-1779, 2014 
Journal Title
Issue Date
Animals ; Carcinogenesis ; Cell Line, Tumor ; Cellular Senescence/physiology* ; Cyclin D1/antagonists & inhibitors* ; Cyclin-Dependent Kinase Inhibitor Proteins/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism* ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Galectin 3/antagonists & inhibitors ; Galectin 3/genetics ; Galectin 3/metabolism* ; Humans ; Mice ; Oncogenes ; Retinoblastoma Protein/genetics ; S-Phase Kinase-Associated Proteins/metabolism
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 p27KIP1 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 p14ARF, p16INK4A, and p21WAF1/CIP1, suggesting that galectin-3-regulated senescence is p27KIP1 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 p27KIP1 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-3high p27KIP1-lowcells. Taken together, our results show that galectin-3 may accelerate gastric tumorigenesis by inhibiting premature senescence.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seok Jun(김석준)
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
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