Tumor suppressor p16 INK4a: Downregulation of galectin-3, an endogenous competitor of the pro-anoikis effector galectin-1, in a pancreatic carcinoma model.
The tumor suppressor p16(INK4a) has functions beyond cell-cycle control via cyclin-dependent kinases. A coordinated remodeling of N- and O-glycosylation, and an increase in the presentation of the endogenous lectin galectin-1 sensing these changes on the surface of p16(INK4a)-expressing pancreatic carcinoma cells (Capan-1), lead to potent pro-anoikis signals. We show that the p16(INK4a)-dependent impact on growth-regulatory lectins is not limited to galectin-1, but also concerns galectin-3. By monitoring its expression in relation to p16(INK4a) status, as well as running anoikis assays with galectin-3 and cell transfectants with up- or downregulated lectin expression, a negative correlation between anoikis and the presence of this lectin was established. Nuclear run-off and northern blotting experiments revealed an effect of the presence of p16(INK4a) on steady-state levels of galectin-3-specific mRNA that differed from decreasing the transcriptional rate. On the cell surface, galectin-3 interferes with galectin-1, which initiates signaling toward its pro-anoikis activity via caspase-8 activation. The detected opposite effects of p16(INK4a) at the levels of growth-regulatory galectins-1 and -3 shift the status markedly towards the galectin-1-dependent pro-anoikis activity. A previously undescribed orchestrated fine-tuning of this effector system by a tumor suppressor is discovered.
Sanchez-Ruderisch
Hugo
H
Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Germany.
Fischer
Christian
C
Detjen
Katharina M
KM
Welzel
Martina
M
Wimmel
Anja
A
Manning
Joachim C
JC
André
Sabine
S
Gabius
Hans-Joachim
HJ
D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D015536:Down-Regulation; D037483:Galectin 1 / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D019941:Cyclin-Dependent Kinase Inhibitor p16; D037483:Galectin 1; D037502:Galectin 3