Autophagy is a cellular response to adverse environment and stress, but its significance in cell survival is not always clear. Here we show that autophagy could be induced in the mammalian cells by chemicals, such as A23187, tunicamycin, thapsigargin, and brefeldin A, that cause endoplasmic reticulum stress. Endoplasmic reticulum stress-induced autophagy is important for clearing polyubiquitinated protein aggregates and for reducing cellular vacuolization in HCT116 colon cancer cells and DU145 prostate cancer cells, thus mitigating endoplasmic reticulum stress and protecting against cell death. In contrast, autophagy induced by the same chemicals does not confer protection in a normal human colon cell line and in the non-transformed murine embryonic fibroblasts but rather contributes to cell death. Thus the impact of autophagy on cell survival during endoplasmic reticulum stress is likely contingent on the status of cells, which could be explored for tumor-specific therapy. Endoplasmic reticulum (ER)3 is critically involved in protein metabolism. Normal ER function is required for the correct folding of many proteins and their post-translational modifications, such as glycosylation and disulfide bond formation. ER stress is induced by the disturbance of the environment in the ER lumen, such as the calcium homeostasis or the redox status, or by the disturbance of ER function, such as glycosylation and transportation to Golgi complex (1). The typical chemicals that induce ER stress include A23187 and thapsigargin, both of which disturb the calcium homeostasis; tunicamycin, which suppresses glycosylation; and brefeldin A, which inhibits transportation to the Golgi complex (1, 2). Thus these chemicals cause protein folding dysfunction, and the accumulated misfolded/unfolded proteins induce ER stress. ER stress is frequently observed in pathological conditions where protein misfolding is caused by genetic mutations either in the molecule to be processed or in the machinery processing the folding (3, 4).The major protective and compensatory mechanism during ER stress is the unfolded protein response (UPR) (1, 5), which leads to translational attenuation and selective up-regulation of a number of bZip transcription factors (1, 5). UPR serves multiple functions, including the assistance of protein folding via the up-regulated ER protein chaperones and the enhanced degradation of misfolded proteins via the up-regulation of molecules involved in the ER-associated degradation pathway (1, 5). However, if the stress is excessive, the compensatory mechanisms may not be able to fully sustain ER function, and ER decompensation could lead to cell death (2, 6). It is not clear whether there are other mechanisms that can regulate ER stress.Macroautophagy (referred as autophagy hereafter) is mainly responsible for the degradation of long-lived proteins and subcellular organelles (7-9). Autophagy is frequently activated in response to adverse environment or stress (10 -13) and has been shown to be involved in many physiological and ...

We isolated and characterized a 2.8-kb, full-length, Arabidopsis thaliana cDNA clone encoding a lipoxygenase. DNA sequence analysis showed that the deduced amino acid sequence of the LOXs (EC 1.13.11.12), dioxygenases that catalyze the hydroperoxidation of polyunsaturated fatty acids containing a cis,cis-1,4-pentadiene-conjugated double-bond system, are present in many if not a11 eukaryotes (Hildebrand et al., 1988;Siedow, 1991). The primary products of LOX-catalyzed reactions, fatty acid hydroperoxides, are typically metabolized into molecules with known or suspected regulatory activity. In mammals, fatty acid hydroperoxides are precursors for the synthesis of bioregulatory molecules including prostaglandins, prostacyclins, leukotrienes, lipoxins, and thromboxanes. These so-called eicosanoids function in inflammation and vasoconstriction/vasodilation, as well as in a number of other mammalian stress responses induced by trauma, disease, or allergy (Schewe et al., 1986; Samuelsson et al., 1987). In higher plants, LOX-derived fatty acid hydroperoxides are

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Recent studies have suggested that the pineal hormone melatonin may protect against breast cancer, and the mechanisms underlying its actions are becoming clearer. Melatonin works through receptors and distinct second messenger pathways to reduce cellular proliferation and to induce cellular differentiation. In addition, independently of receptors melatonin can modulate oestrogen-dependent pathways and reduce free-radical formation, thus preventing mutation and cellular toxicity. The fact that melatonin works through a myriad of signalling cascades that are protective to cells makes this hormone a good candidate for use in the clinic for the prevention and/or treatment of cancer. This review summarises cellular mechanisms governing the action of melatonin and then considers the potential use of melatonin in breast cancer prevention and treatment, with an emphasis on improving clinical outcomes.