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Overexpression of Fas ligand (FasL) in cancer cells elicits potential antitumor effects via recruitment of neutrophils. Conversely, FasL-expressing tumors may counterattack tumor-infiltrating lymphocytes by delivering apoptotic death signals via Fas/FasL interactions, which may lead to tumor escape. In order to distinguish the role of FasL in antitumor activity and tumor progression, Lewis lung carcinoma cells (LLC-1) were used to establish the cell line LLC-FasL, in which FasL expression was repressed by doxycycline (Dox) treatment and induced in the absence of Dox. LLC-FasL cells promote tumor regression when expressing FasL, whereas tumor outgrowth is observed by depletion of FasL expression. To investigate whether initial expression of FasL during tumor formation is critical for FasL-mediated tumor regression, Dox-treated LLC-FasL cells were inoculated into Dox-treated mice, but Dox treatment was stopped 5 days after inoculation. When low cell numbers were inoculated, we observed 80% survival and no tumor formation, whereas no mice survived inoculation with high cell numbers, despite the delayed induction of FasL by Dox withdrawal. The inoculation of a high density of cells may establish a favorable tumor microenvironment before the expression of FasL. Our findings demonstrate that FasL may elicit antitumor activity when it is initially present on injected cancer cells and thus can act prior to tumor microenvironment formation. Furthermore, a well-established tumor microenvironment abrogates FasL-mediated antitumor activity.

Background Atypical antipsychotics such as olanzapine often cause metabolic side effects such as obesity and diabetes, leading to an increased risk of nonalcoholic fatty liver disease. The aim of the present study was to investigate the effects of olanzapine treatment on hepatic lipid metabolism and its possible relationship with adipose tissue status. Methods Using a female rat model, we investigated the effects of chronic olanzapine administration on the regulation of carbohydrate and lipid metabolism including lipid biosynthesis, oxidation, efflux, and lipolysis in liver and adipose tissue. Results The body weight, liver mass and visceral adiposity after olanzapine treatment (2 mg/kg) for five weeks were not significantly different compared with vehicle controls. The serum level of triglycerides was higher in the vehicle controls than in olanzapine-treated rats. Unexpectedly, olanzapine treatment did not reduce glucose tolerance in our model. The expression of functional thermogenic protein uncoupling protein 1 (UCP1) was increased in brown adipose tissue (BAT) of the olanzapine group. Additionally, olanzapine treatment also reduced adipose inflammation in white adipose tissue (WAT). The transcription factor sterol regulatory element-binding protein (SREBP)-1c, a key early regulator of lipogenesis, was downregulated following olanzapine treatment. The expression of genes related to the triglycerides synthesis apparatus in the liver was upregulated in the olanzapine group. Olanzapine treatment induced genes involved in PPAR-α signaling and mitochondrial fatty acid oxidation in response to increased ATGL-mediated lipolysis in the liver. Conclusion Together, our findings suggest a complicated link between olanzapine therapy and metabolic disturbance and may garner interest in assessing the action of antipsychotic-induced metabolic disturbances.