The major polyphenol in green tea, (-)-epigallocatechin-3-gallate (EGCG), has been shown to prevent carcinogenesis. We have identified a receptor that mediates the anticancer activity of EGCG. Expression of the metastasis-associated 67-kDa laminin receptor confers EGCG responsiveness to cancer cells at physiologically relevant concentrations. Experiments using surface plasmon resonance demonstrate binding of EGCG to the 67-kDa laminin receptor with a nanomolar K (d) value.

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It is poorly understood how sensory systems memorize the intensity of sensory stimulus, compare it with a newly sensed stimulus, and regulate the orientation behaviour based on the memory. Here we report that Caenorhabditis elegans memorizes the environmental salt concentration during cultivation and exhibits a strong behavioural preference for this concentration. The right-sided amphid gustatory neuron known as ASER, senses decreases in salt concentration, and this information is transmitted to the postsynaptic AIB interneurons only in the salt concentration range lower than the cultivation concentration. In this range, animals migrate towards higher concentration by promoting turning behaviour upon decreases in salt concentration. These observations provide a mechanism for adjusting the orientation behaviour based on the memory of sensory stimulus using a simple neural circuit. A ll living animals are endowed with the capacity to seek optimal ambient conditions. Such behaviour requires memorizing the intensity of sensory stimulus associated with favourable conditions, recognizing the spatio-temporal changes of the stimulus intensity under current conditions, comparing it with the memorized stimulus intensity and regulating the motor output to generate a movement towards a preferred direction. However, in most sensory systems how stimulus intensity is memorized and how distinct orientation behaviours are generated depending on the memory have been poorly explored.Sodium chloride was identified as a chemoattractant for C. elegans 1 . Based on this view the mechanisms of salt chemotaxis has been examined for decades. Amphid taste neurons ASE, which consist of two morphologically symmetric neurons on the left (ASEL) and the right (ASER), have a predominant role in chemotaxis to NaCl and other inorganic salts 2-4 . Calcium imaging experiments showed that these neurons are functionally asymmetric: ASER is depolarized by decreases in salt concentration, while ASEL responds to increases 5 . As activation of ASER and ASEL promotes redirecting turns and forward locomotion, respectively, it was suggested that the right and the left neurons have distinct roles but act in concert for migrating up salt gradient 5 . Through another line of studies on the migration behaviours, two distinct behavioural mechanisms that drive animals towards higher salt concentration have been characterized so far (see below) 6,7 . Despite these sets of knowledge, the physiological and mechanistic properties of the information flow for salt chemotaxis downstream of the sensory neurons have not been obvious, as ASEL and ASER form synapses onto overlapping targets (Fig. 1a).Meanwhile, we have previously shown that pairing starvation with exposure to NaCl causes salt avoidance learning in C. elegans 8 . The insulin signalling pathway components, DAF-2 insulin receptor, AGE-1 phosphoinositide 3-kinase and AKT-1 AKT kinase, are required in ASER for this learning 9 . Activation of the Gq/DAG/PKC signalling pathway consisting of EGL-30 Gq, diacylglycer...

The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.