Negative Regulation of Neuroblastoma Cell Growth by Carbohydrate-dependent Surface Binding of Galectin-1 and Functional Divergence from Galectin-3

Abstract Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I), and remains incurable. Therefore, novel treatments are urgently needed. Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signaling pathways. The distribution of galectins is quite diverse, and their expression in various leukocytes has been observed. To determine whether expression of galectins in T cells correlates with HTLV-I infection, we surveyed a number of uninfected and HTLV-I-infected T-cell lines for galectin-3, -8, and -9 expression by RT-PCR. Expression of galectin-8 did not correlate with HTLV-I infection. Galectin-3 was abundantly expressed in HTLV-I-infected T-cell lines and primary ATL cells, but not in uninfected T-cell lines. In contrast, galectin-9 was abundantly expressed in uninfected T-cell lines and normal PBMCs, but not in HTLV-I-infected T-cell lines and primary ATL cells. HTLV-I transformed protein, Tax, did not affect the expression of galectin-3 and -9. It was previously shown that galectin-8 and -9 are proapoptotic proteins. We found that galectin-9 prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells compared with galectin-8. Galectin-9 induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, and Cdc25C, and apoptosis by reducing the expression of XIAP and c-IAP2. Most of these genes are known to be regulated by NF-κB, which plays a critical role in oncogenesis by HTLV-I. Galectin-9 suppressed phosphorylation of IκBα. Most importantly, treatment with galectin-9 reduced tumor formation from an HTLV-I-infected T-cell line, HUT-102, when these cells were inoculated s.c. into severe combined immunodeficient mice. Our results suggest that galectin-9 may be a new approach for management of ATL.

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The role of EGFR trafficking in neuroblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.20003 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 20003-20003

Author(s):

P. E. Zage ◽

Q. Yan ◽

L. Zeng ◽

A. J. Bean

Keyword(s):

Growth Factor ◽

Cell Growth ◽

Cell Lines ◽

Neuroblastoma Cell ◽

Growth Factor Receptor ◽

Growth Factor Receptors ◽

Human Neuroblastoma ◽

Degradation Rates ◽

Neuroblastoma Cell Lines

20003 Background: Signaling through growth factor receptors is important in neuroblastoma pathogenesis. Chromosome 1p36 is commonly deleted in neuroblastoma tumors and is associated with a poor prognosis. UBE4B, a gene in 1p36, has been reported mutated in high- risk neuroblastoma. We have found a direct interaction between UBE4B and hrs, a protein required for epidermal growth factor receptor (EGFR) trafficking, suggesting a link between EGFR trafficking and neuroblastoma pathogenesis. We have analyzed the role of UBE4B in the EGFR pathway in neuroblastoma cell lines. Methods: The expression of UBE4B, hrs and EGFR were analyzed by quantitative Western blot in a panel of 7 human neuroblastoma cell lines (SHEP, SKNAS, SKNSH, KCNR, SY5Y, LA155N, NGP). EGFR degradation rates were determined by examining the kinetics of cellular EGFR depletion following a pulse of ligand. Results: UBE4B levels were lowest in SKNAS and highest in NGP cells. Hrs levels were lowest in SKNSH cells and higher in other cell lines. EGFR levels were lowest in NGP and KCNR and highest in SKNAS cells. UBE4B levels were correlated with known 1p deletions. EGFR degradation rates were slowest in SKNAS cells and therefore correlated with cellular UBE4B levels. The low degradation rates were correlated with high cellular levels of EGFR. Conclusions: Expression levels of UBE4B are correlated in neuroblastoma cell lines with chromosome 1p deletions. Cell lines with lower levels of UBE4B degrade EGFR at a markedly slower rate, correlated with higher cellular EGFR levels. We hypothesize that UBE4B affects cell growth by interacting with hrs, directing EGFR for degradation. In its absence the ability of a cell to sort growth factor receptors for degradation is inhibited, resulting in growth factor receptor overabundance and uncontrolled cell growth. These results support the testing of EGFR inhibitors in a future phase I trial for children with neuroblastoma. No significant financial relationships to disclose.

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