Barkan Batya, Cox Adrienne D, Kloog Yoel
Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Oncotarget. 2013 Feb;4(2):256-68. doi: 10.18632/oncotarget.844.
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.
半乳糖凝集素是一类β-半乳糖苷结合凝集素，可在细胞外和细胞内发挥多种作用。半乳糖凝集素-7和半乳糖凝集素-1在不同细胞类型中对增殖和存活表现出相反的作用。半乳糖凝集素-7是一种p53诱导基因，也是细胞凋亡的增强剂，而半乳糖凝集素-1在几种癌症类型中诱导肿瘤发生并赋予细胞抗凋亡能力。我们在此表明，在源自神经纤维瘤蛋白缺陷（Nf1(-/-)）的恶性外周神经鞘瘤（MPNST）的细胞中，S-反式，反式-法尼基硫代水杨酸（FTS；Salirasib）对Ras的抑制作用改变了半乳糖凝集素的表达模式。虽然FTS降低了活性Ras和半乳糖凝集素-1的表达水平，但它显著增加了半乳糖凝集素-7的mRNA和蛋白表达水平。半乳糖凝集素-7的积累是通过JNK抑制介导的，推测这是由于观察到的p53诱导所致，并且受到AP-1抑制剂JDP2的负调控。半乳糖凝集素-7自身的表达降低了ST88-14细胞中的Ras激活，并使它们对细胞凋亡敏感。观察到的半乳糖凝集素表达模式的这种转变以及随之而来的从细胞增殖到细胞凋亡的转变代表了FTS抑制Ras的一种新模式。鉴于增强的细胞增殖和细胞凋亡缺陷都是人类癌症的主要特征，并且在MPNST对抗癌治疗的抗性中起核心作用，这似乎可能是一个重要现象。这些发现表明，FTS单独或与化疗药物联合使用，可能值得开发作为MPNST的一种可能治疗方法。
