Ras inhibition boosts galectin-7 at the expense of galectin-1 to sensitize cells to apoptosis.

Abstract

Galectins are a family of β-galactoside-binding lectins that exert diverse extracellular and intracellular effects. Galectin-7 and galectin-1 show opposing effects on proliferation and survival in different cell types. Galectin-7 is a p53-induced gene and an enhancer of apoptosis, whereas galectin-1 induces tumorigenicity and resistance to apoptosis in several types of cancers. We show here that in cells derived from neurofibromin-deficient (Nf1(-/-)) malignant peripheral nerve sheath tumors (MPNSTs), Ras inhibition by S-trans,trans-farnesylthiosalicylic-acid (FTS; Salirasib) shifts the pattern of galectin expression. Whereas FTS decreased levels of both active Ras and galectin-1 expression, it dramatically increased both the mRNA and protein expression levels of galectin-7. Galectin-7 accumulation was mediated through JNK inhibition presumably resulting from the observed induction of p53, and was negatively regulated by the AP-1 inhibitor JDP2. Expression of galectin-7 by itself decreased Ras activation in ST88-14 cells and rendered them sensitive to apoptosis. This observed shift in galectin expression pattern together with the accompanying shift from cell proliferation to apoptosis represents a novel pattern of Ras inhibition by FTS. This seems likely to be an important phenomenon in view of the fact that both enhanced cell proliferation and defects of apoptosis constitute major hallmarks of human cancers and play a central role in the resistance of MPNSTs to anti-cancer treatments. These findings suggest that FTS, alone or in combination with chemotherapy agents, may be worth developing as a possible treatment for MPNSTs.

• Authors: Batya Barkan, Adrienne D Cox, Yoel Kloog
• Journal: Oncotarget (Oncotarget) Vol. 4 Issue 2 Pg. 256-68 (Feb 2013) ISSN: 1949-2553 [Electronic] United States
• PMID: 23530091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Galactosides
• Galectin 1
• Galectins
• LGALS1 protein, human
• LGALS7 protein, human
• Neurofibromin 1
• Salicylates
• beta-galactoside
• farnesylthiosalicylic acid
• Farnesol
• ras Proteins

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Growth Processes (drug effects)
• Farnesol (analogs & derivatives, pharmacology)
• Galactosides (genetics, metabolism)
• Galectin 1 (biosynthesis, genetics, metabolism)
• Galectins (biosynthesis, genetics, metabolism)
• Humans
• Nerve Sheath Neoplasms (drug therapy, genetics, pathology)
• Neurofibromin 1 (deficiency, genetics)
• Salicylates (pharmacology)
• Transcription, Genetic
• ras Proteins (antagonists & inhibitors, metabolism)