Cryptotanshinone Prevents the Binding of S6K1 to mTOR/Raptor Leading to the Suppression of mTORC1-S6K1 Signaling Activity and Neoplastic Cell Transformation

Cryptotanshinone is known for its inhibitory activity against tumorigenesis in various human cancer cells. However, exact mechanisms underlying the anticancer effects of cryptotanshinone are not fully elucidated. Here, we propose a plausible molecular mechanism, wherein cryptotanshinone represses rapamycin-sensitive mTORC1/S6K1 mediated cancer cell growth and cell transformation. We investigated the various effects of cryptotanshinone on the mTORC1/S6K1 axis, which is associated with the regulation of cell growth in response to nutritional and growth factor signals. We found that cryptotanshinone specifically inhibited the mTORC1-mediated phosphorylation of S6K1, which consequently suppressed the clonogenicity of SK-Hep1 cells and the neoplastic transformation of JB6 Cl41 cells induced by insulin-like growth factor-1. Finally, we observed that cryptotanshinone prevented S6K1 from binding to the Raptor/mTOR complex, rather than regulating mTOR and its upstream pathway. Overall, our findings provide a novel mechanism underlying anti-cancer effects cryptotanshinone targeting mTORC1 signaling, contributing to the development of anticancer agents involving metabolic cancer treatment.

Cryptotanshinone Prevents the Binding of S6K1 to mTOR/Raptor Leading to the Suppression of mTORC1-S6K1 Signaling Activity and Neoplastic Cell Transformation

Cryptotanshinone is known for its inhibitory activity against tumorigenesis in various human cancer cells. However, exact mechanisms underlying the anticancer effects of cryptotanshinone are not fully elucidated. Here, we propose a plausible molecular mechanism, wherein cryptotanshinone represses rapamycin-sensitive mTORC1/S6K1 mediated cancer cell growth and cell transformation. We investigated the various effects of cryptotanshinone on the mTORC1/S6K1 axis, which is associated with the regulation of cell growth in response to nutritional and growth factor signals. We found that cryptotanshinone specifically inhibited the mTORC1-mediated phosphorylation of S6K1, which consequently suppressed the clonogenicity of SK-Hep1 cells and the neoplastic transformation of JB6 Cl41 cells induced by insulin-like growth factor-1. Finally, we observed that cryptotanshinone prevented S6K1 from binding to the Raptor/mTOR complex, rather than regulating mTOR and its upstream pathway. Overall, our findings provide a novel mechanism underlying anti-cancer effects cryptotanshinone targeting mTORC1 signaling, contributing to the development of anticancer agents involving metabolic cancer treatment.

MPO Gene Polymorphism in Behcet's Disease / 대한류마티스학회지

OBJECTIVE: Behcet's disease (BD) is a systemic vasculitis in which hyperfunction of neutrophils is one of the major pathophysiologic features. Myeloperoxidase (MPO) is an important neutrophilic lysosomal enzyme and has been implicated in tissue damage of BD. As the A allele of -463G/A polymorphism of the MPO gene is associated with diminished activity of MPO, we analyzed the association of -463G/A polymorphism of the MPO gene with BD. METHODS: We analyzed -463G/A polymorphism of the MPO gene in BD patients (n=101) and controls (n=138). Genotype of the MPO gene at position -463 was determined by PCR-RFLP assay using genomic DNA. RESULTS: The allele frequency of -463G/A polymorphism of the MPO gene did not deviate from the Hardy-Weinberg expectation in both BD patients and controls. There were no statistically significant differences in genotype distribution and allele frequency between patients and controls at position -463 (p=0.761 and p=0.549 respectively). Analysis of genotype distribution and allele frequency of the -463G/A according to sex did not show any difference between patients and controls. There were no statistically significant differences in clinical manifestations of BD among different genotypes. CONCLUSION: The present data indicate that the -463G/A polymorphism of the MPO gene was not associated with the susceptibility to and clinical manifestations of BD in Korea.

The Synthesis and MR Properties of New Macromolecular MR Contrast Agent

PURPOSE: To evaluate the NMR relaxation properties and imaging characteristics of tissue-specificity for a newly developed macromolecular MR agent. MATERIALS AND METHODS: Phthalocyanine (PC) was chelated with paramagnetic ion, Mn. 2.01g(5.2 mmol) of Phthalocyanine was mixed with 0.37g (1.4 mmol) of Mn chloride at 310 degrees C for 36 hours and then purified by chromatography (CHC13/CH3OH 98/2 v/v, Rf, 0.76) to obtain 1.04g (46%) of MnPC (molecular weight = 2000d), The T1/T2 relaxivity of MnPC was measured in 1.5T(64 MHz) MR using 0.1 mM MnPC. The MR image characteristics of MnPC was evaluated using spin-echo (TR/TE = 500/14 msec) and gradient-echo (FLASH) (TR/TE = 80/4 msec, flip angle = 60) techniques in 1.5T MR scanner. The images of rabbit liver were obtained every 10 minutes up to 4 hours. To study the effect of concentration on image, 20 mM, 50 mM, 100 mM of MnPC were tested. RESULTS: The relaxivities of MnPC at 1.5T (64MHz) were R1 = 7.28 mM-1S-1, R2 = 55.56 mM-1S-1. Compared to the values of Gd-DTPA (R1[= 4.8 mM-1S-1), R2[= 5.2 mM-1S-1]), both T1/T2 relaxivities of MnPC were higher than those of Gd-DTPA. For both of SE and FLASH techniques, the contrast enhancement reached maximum at 10 minutes after bolus injection and the enhancement continued for more than 2 hours. When compared with small molecular weight liver agents such as Gd-EOB-DTPA, Gd-BOPTA and MnDPDP, MnPC was characterized by more prolonged enhancement time. The time course of MR images also revealed biliary excretion of MnPC. CONCLUSION: We developed a new macromolecular MR agent, MnPC. The relaxivities of MnPC were higher than those of small molecular weight Gd-chelate. Hepatic uptake and biliary excretion of MnPC suggests that this agent is a new liver-specific MR agent.

Multi-Component Relaxation Study of Human Brain Using Relaxographic Analysis

PURPOSE: To demonstrate that the relaxographic method provides additional information such as the distribution of relaxation times and water content which are poentially applicable to clinical medicine. MATERIALS AND METHODS: First, the computer simulation was performed with the generated relaxation data to verify the accuracy and reliablility of the relaxographic method (CONTIN). Secondly, in order to see how well the CONTIN quantifies and resolves the two different T1 environments, we calculated the oil to water peak area ratios and identified peak positions of T1-distribution curve of the phantom solutions, which consist of four centrifugal tubes (10ml) filled with the compounds of 0, 10, 20, 30% of corn oil and distilled water, using CONTIN. Finally, inversion recovery MR images for a volunteer are acquired for each TI ranged from 40 to 1160 msec with TR/TE=2200/20 msec. From the 3 different ROIs (GM, WM, CSF), CONTIN analysis was performed to obtain the T1-distribution curves, which gave peak positions and peak area of each ROI location. RESULTS: The simulation result shows that the errors of peak positions were less in the higher peak (centered T1=600 msec) than in the lower peak (centered T1=150 msec) for all SNR but the errors of peak areas were larger in the higher peak than in the lower peak. The CONTIN analysis of the measured relaxation data of phantoms revealed two peaks between 20 and 60 msec and between 500 and 700 msec. The analysis gives the peak area ratio as oil 10%: oil 20%: oil 30%=1:1.3:1.9, which is different from the exact ratio, 1:2:3. For human brain, in ROI 3 (CSF), only one component of -distributions was observed whereas in ROI 1 (GM) and in ROI 2 (WM) we observed two components of T1-distribution. For the WM and CSF there was great agreement between the observed T1-relaxation times and the reported values. CONCLUSION: we demonstrated that the relaxographic method provided additional information such as the distribution of relaxation times and water content, which were not available in the routine relaxometry and T1/T2 mapping techniques. In addition, these additional information provided by relaxographic analysis may have clinical importance.