Notch ligand Delta-like 1 promotes the metastasis of melanoma by enhancing tumor adhesion.

Notch signaling plays a vital role in tumorigenicity and tumor progression by regulating proliferation, invasion, and the tumor microenvironment. Previous research by our group indicated that Notch ligand Delta-like 1 (Dll1) is involved in angiogenesis in melanoma, and we noticed that it took a longer time to trypsinize Dll1-expressing B16 melanoma cells than the control cells. In this article, we extended our study to investigate the effects of Dll1 on tumor cell adhesion and metastasis. Dll1 overexpression activated Notch signaling in B16 tumor cells and significantly enhanced the adhering capacity of B16 tumor cells both in vitro and in vivo. B16-Dll1 cells also had a higher metastatic potential than their counterpart in the mouse model of lung metastasis. Along with increased Dll1 expression, N-cadherin, but not E-cadherin, was upregulated in B16-Dll1 cells. These data suggested that Notch ligand Dll1 may enhance the adhesion and metastasis of melanoma cells by upregulation of N-cadherin.

Notch ligand Delta-like 1 promotes the metastasis of melanoma by enhancing tumor adhesion

Notch signaling plays a vital role in tumorigenicity and tumor progression by regulating proliferation, invasion, and the tumor microenvironment. Previous research by our group indicated that Notch ligand Delta-like 1 (Dll1) is involved in angiogenesis in melanoma, and we noticed that it took a longer time to trypsinize Dll1-expressing B16 melanoma cells than the control cells. In this article, we extended our study to investigate the effects of Dll1 on tumor cell adhesion and metastasis. Dll1 overexpression activated Notch signaling in B16 tumor cells and significantly enhanced the adhering capacity of B16 tumor cells both in vitro and in vivo. B16-Dll1 cells also had a higher metastatic potential than their counterpart in the mouse model of lung metastasis. Along with increased Dll1 expression, N-cadherin, but not E-cadherin, was upregulated in B16-Dll1 cells. These data suggested that Notch ligand Dll1 may enhance the adhesion and metastasis of melanoma cells by upregulation of N-cadherin.

Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2.

Apoptosis-inducing factor (AIF) represents a caspase-independent apoptotic pathway in the cell, and a mitochondrial localization sequence-truncated AIF (AIFDelta1-120) can be relocated from the cytoplasm to the nucleus and exhibit a constitutive proapoptotic activity. Here, we generated a chimeric immuno-AIF protein, which comprised an HER2 antibody, a Pseudomonas exotoxin translocation domain and AIFDelta1-120. Human Jurkat cells transfected with the immuno-AIF gene could express and secrete the chimeric protein, which selectively recognized HER2-overexpressing tumor cells and was endocytosed. Subsequent cleavage of truncated AIF from immuno-AIF and its release from the internalized vesicles resulted in apoptosis of tumor cells. Intramuscular injection of the immuno-AIF gene caused significant suppression of tumors and substantially prolonged mice survival in an HER2-overexpressing xenograft tumor model. Our study demonstrates the feasibility of the immuno-AIF gene as a novel approach to treating cancers that overexpress HER2.

[The effect of melatonin on enhancing immune function and inhibiting the ability of NO over-release in morphine dependent mice].

AIM: To observe the effects and mechanism of melatonin (MT) on the immune function of morphine dependent mice. METHODS: A physical dependent mice model was established by repeated subcutaneous injection of morphine. The intensity of morphine withdrawal syndrome was evaluated according to the weight of immune organs, the proliferation reaction of stimulated splenic lymphocytes by Con A, the phagoindex of blood primed macrophages and the content of NO induced in the peritoneal macrophage (pM phi). RESULTS: MT reversed the inhibitory effect of morphine on the proliferation ability of splenic lymphocytes and enhanced the phagocytosis of macrophages of morphine dependent mice obviously and prevented the over-release of NO from pM phi. The enhancing effects of MT on the phagocytosis can be prevented by naloxon. CONCLUSION: MT can significantly enhance the immune function of morphine dependent mice and inhibit NO excessive release from pM phi.

[Influence of intracerebroventricular injection of sodium nitroprusside L-arginine and NG-nitro-L-arginine on cardiovascular activity in conscious rats].

In order to study the cardiovascular effect of NO in conscious rats, sodium nitroprusside (SNP), the precursor of NO (L-Arginine, Arg-Arg) and one of the inhibitor of NOS (NG-nitro-L-arginine, NNLA) were intracerebroventricularly (icv) injected. Our experimental results indicated that, an apparent dose-dependent hypertensive effect was produced by icv administration of SNP (8, 16, 32 and 32 micrograms), a tachycardiac effect was also produced at the same time. In addition, hypertension and tachycardia were produced by icv L-arginine and the dipeptide Arg-Arg. Furthermore a hypotensive and bradycardiac effect can be produced by icv NNLA. These results suggest that there is a positive effect on cardiovascular activity due to increase of endogeneuse NO in the rat brain and a negative effect on cardiovascular activity due to decrease of endogeneuse NO in the rat brain.

[The cardiovascular reactions mediated by TPA and tamoxifen in spinal cord of conscious rats].

Intrathecal administration (ith) of phorbol 12-myristate (TPA), an activator of protein kinase C, (31.24, 26.5, 125 and 250 ng/10 micrograms) to conscious rats produced a marked dose-dependent pressor effect without significant change in heart rate (HR). Intrathecal administration of tamoxifen (3.125, 6.5 and 100 micrograms/10 microliters), one of the inhibitors of protein kinase C, produced a marked dose-dependent hypotensive effect. Intrathecal injection of exogenous DBcAMP (12.5, 25, 50 and 100 micrograms/10 microliters) also increased the mean arterial blood pressure (mABP) and markedly lowered HR. It was further observed that, based on the effect of DBcAMP (25 micrograms/10 microliters), the pressor effect of four doses of TPA can be augmented. The results indicate that TPA in spinal cord may exert hypertensive effect via activation of PKC and tamoxifen may exert a hypotensive effect via inhibition of PKC. In addition, the pressor effect of TPA could be augmented by preadministration of DBcAMP.

[The depressor effect of intracerebroventricular injection of BQ123 and endothelin (ET)--antiserum on hypertensive rats produced by aorta stenosis and hypersaline uptake].

An experimental model of hypertensive rat was made by abdominal aorta stenosis and hypersaline uptake. The blood pressure was significantly decreased by intracerebroventricular injection (i.c.v.) of BQ123 a potent antagonist of ET-1 receptor, in a dose-dependent manner. Negative chronotropic effect on the heart was produced by high dose of BQ123, while the depressor effect was produced by i.c.v. ET-antiserum. These results indicate that endothelin in CNS may play an important role in the pathological physiology of hypertension.

Serotonin receptor subtypes in spinal antinociception in the rat.

The aim of the present study was to clarify the subtypes of serotonin (5-HT) receptors involved in spinal antinociception in the rat. 1) Intrathecal (i.t.) injection of 5-HT (25-200 micrograms) produced a dose-dependent increase in tail-flick latency. 2) Intrathecal injection of fluoxetine, a 5-HT uptake blocker (25-40 micrograms), resulted in a bell-shaped dose-related antinociception with peak effects occurring at 10 micrograms. 3) A bell-shaped antinociceptive effect was obtained by i.t. injection of the 5-HT1A agonist (+)-hydroxy-2-(di-N-propylamino)tetralin (0.25-2 micrograms), with the maximal effect occurring at 0.5 micrograms, which can be prevented by the 5-HT1A antagonist spiperone (25 micrograms i.t.). 4) A similar dose-response curve was obtained following the i.t. injection of the 5-HT1B agonist 1-[3-(trifluoromethyl)phenyl]-piperazine maleate (1-125 micrograms) with the maximal effect observed at 25 micrograms. 5) Neither the 5-HT2 agonist (+/-)-alpha-methyl-5-HT-maleate nor the 5-HT3 agonist (+/-)-2-methyl-5-HT-maleate produced significant antinociceptive effects at doses up to 50 micrograms. Spontaneous tail-flicks emerged at doses higher than 50 micrograms. 6) The antinociceptive effect induced by 5-HT (200 micrograms i.t.) could be attenuated dose-dependently either by the 5-HT1A antagonist spiperone (5 and 25 micrograms i.t.) or by the 5-HT1C/2 antagonist mianserin (0.5-50 micrograms i.t.), but not by the 5-HT2 antagonist 1-(1-naphthyl)piperazine hydrochloride or the 5-HT3 antagonist 3-tropanyl-indole-3-carboxylate.(ABSTRACT TRUNCATED AT 250 WORDS)