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Effects of Mifepristone and Tamoxifen on Calcium Modulation in DU-145 Prostate Cancer Cells
Yeo-Reum Kim(김여름),Byeong Gee Kim(김병기) 한국생명과학회 2010 생명과학회지 Vol.20 No.9
Mifepristone (MIF)와 Tamoxifen (TAM)은 각각 전립선암과 유방암치료제로 오랫동안 사용되고 있다. MIF는 안드로겐수용체(AR) 양성인 세포와 음성이 세포 모두에서 세포사멸을 유도하며, TAM 은, 리간드-수용체작용 기작의 다양한 특성에 의하여 에스트로겐(ER) 양성인 세포뿐 만 아니라 다른 종류의 암세포에서도 세포사멸을 유도하는 것으로 알려져 있다. 본 연구에서는 AR 음성인 DU-145 전립선암세포에 있어서, MIF와 TAM의 세포독성이 세포 내 칼슘농도 변화에 기인된 세포사멸기작에 의한 것임을 보여준다. MIF와 TAM을 처리시 세포성장은 농도와 시간의존적으로 감소하였으며, confocal laser scanning microscopy (CLSM)과 fluorescence-activated cell sorting (FASC)로 세포를 분석한 결과 각각 MIF와 TAM을 2일간 처리한 세포에서 세포사멸이 진행되는 것을 관찰하였다. 세포독성효과를 비교했을 경우, TAM이 MIF 보다 강하게 작용하였다. MIF와 TAM을 처리한 세포 내 칼슘변화 측정 시, 칼슘농도 또한 처리 약물의 농도와 시간 의존적으로 증가하였다. 1.5 mM 칼슘배지와 칼슘 제거된 배지에서의 실험결과를 비교한 바, 세포 내 칼슘증가는 외부로부터의 유입에 의한 것으로 생각된다. 세포 독성효과와 마찬가지로 칼슘증대 효과 역시 TAM에서 뚜렷하게 나타났다. 수용체 매개 세포사멸기작의 초기에 관여하는 procaspase-8은 MIF 처리 시 뚜렷이 활성화 되었으나, TAM의 경우 활성화가 MIF의 경우에 비해 강하지 못하였다. 그러나, 세포사멸의 중추적인 역할을 하는 caspase-3은 TAM 을 처리한 세포에 있어서 활성 정도가 훨씬 높았다. 세포사멸과정의 중요한 조절 단백질인 Bcl-2 그룹단백질의 발현을 조사해 본 결과, 세포사멸 억제단백질인 Bcl-2의 발현은 MIF, TAM 처리 시 동일하게 감소한 반면, 촉진단백질인 Bax의 발현은 2-3배 가량 증대되었다. 이상의 결과로 보아 MIF와 TAM은 세포 내 칼슘조절을 통하여 세포사멸을 유도하나, 세포사멸의 초기단계는 MIF와 TAM이 서로 다른 경로를 경유할 가능성이 있는 것으로 생각된다. Mifepristone (MIF) and Tamoxifen (TAM) have been used in the treatment of prostate cancer and breast cancer for more than a decade. MIF can induce apoptosis in both AR-positive and ?negative prostate cancer cells. Because of its pleiotropic ligand-receptor properties, TAM exerts cytotoxic activity in estrogen (ER)-positive and various ER?negative cancer cells. However, the molecular mechanisms of these two substances are not yet clear. In the present work, we report that the cytotoxic effects of MIF and TAM are due to the modulation of intracellular Ca<SUP>2+</SUP> level in DU-145, androgen-insensitive cells. When the cells were treated with micromolar concentrations of either MIF or TAM, the growth and viability were significantly decreased in a dose- and time-dependent manner. The apoptosis induced by MIF or TAM was further proved and analyzed by confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS). In the cells cultivated in a normal 1.5 mM Ca<SUP>2+</SUP> medium, both MIF and TAM also induced an increase of the intracellular Ca<SUP>2+</SUP> level in a dose-dependent fashion. Since a change in calcium level could not be found in cells of the Ca<SUP>2+</SUP>-free medium, the increase of intracellular Ca<SUP>2+</SUP> level might be due to an increase in extracellular calcium uptake. Our results show that the apoptotic effect was more prominent in TAM treatment compared to MIF treatment in DU-145 cells. The above findings might be due to the difference in the uppermost pathways of apoptosis induced by either MIF or TAM. When we checked the level of procaspase-8 activation, TAM showed minor level of activation, as opposed to MIF, which exerted strong activation. In both treatments, the levels of anti-apoptotic protein Bcl-2 decreased, and pro-apoptotic protein Bax level increased more than 2-fold. The activation of caspase-3, a key protease enzyme in the downstream pathway of apoptosis, was much higher in the cells treated with TAM, compared to the MIF treatment. The overall apoptotic activity shown in the present work was closely related to intracellular Ca<SUP>2+</SUP> concentration levels. Therefore, the cytotoxic activity induced by MIF and TAM might have been due to intracellular calcium modulation.
Yeo-Reum Park,Hye-Bin Par,Mi-Jeong Kim,Seunghyung Lee,Choon-Keun Park,Boo-Keun Yang,Hee-Tae Cheong 한국동물생명공학회(구 한국동물번식학회) 2018 발생공학 국제심포지엄 및 학술대회 Vol.2018 No.06
We examined the effect of endoplasmic reticulum (ER) stress inhibitor treatment during somatic cell nuclear transfer (SCNT) process on the reprogramming efficiency of porcine embryos. ER stress inhibitors such as Salubrinal (200 nM) and tauroursodeoxychloic acid (TUDCA, 100 μM) were added to the manipulation medium and holding medium. Porcine SCNT embryos were sampled at the 1-cell stage for mRNA extraction. The expression of x-box binding protein 1 (Xbp1), ER stress-associated genes and apoptotic genes were confirmed by RT-PCR or RT-qPCR. The levels of X-box binding protein 1 (Xbp1) splicing and the expression of ER stress-associated genes were significantly decreased by TUDCA treatment at the 1-cell stage of SCNT embryos (p<0.05). The expression of ER stress-associated genes was also slightly decreased by a combination treatment of salubrinal and TUDCA (Sal+TUD). The expression levels of Caspase-3 and Bcl2-associated X protein (Bax) mRNA were also significantly lower in TUDCA and Sal+TUD groups (p<0.05). The blastocyst formation rate (20.2%, 41/203) and the mean cells number in blastocysts (63.0±7.2, p<0.05) were significantly increased in the TUDCA treatment group compared with the control group (12.6% and 41.7±3.1, p<0.05). These results show that the treatment of ER stress inhibitor, especially TUDCA, during SCNT process can inhibit cellular damages and enhance in vitro development of SCNT embryos by reducing ER stress.
Yeo, A-Reum,Lee, Jung-Lim,Tae, In-Hwan,Park, Seok-Rae,Cho, Young-Ho,Lee, Bong-Ho,Shin, Hyeon-Cheol,Kim, Seong-Ho,Yoo, Yung-Choon The Korean Society of Food Science and Nutrition 2012 Preventive Nutrition and Food Science Vol.17 No.1
The inhibitory effect of polyphenol extracts (Seapolynol$^{TM}$, SPN) of the marine brown algae Ecklonia cava and dieckol, a major component of SPN, on hyperlipidemia was investigated in ICR mice fed a high-fat diet (HFD) for five weeks. For analysis of the anti-hyperlipidemic effects of SPN and dieckol, these two agents were given orally on a daily basis to HFD-fed mice for four weeks, starting one week after the beginning of HFD feeding. Groups administered with SPN as well as dieckol showed lower body weight gains than the HFD only group. Administration of SPN and dieckol also resulted in a significant reduction of the level of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein (LDL) cholesterol in the serum of HFD-fed mice. In Oil Red O staining using 3T3-L1 preadipocytes, it was shown that both SPN and dieckol markedly inhibited lipid accumulation of 3T3-L1 cells. Furthermore, SPN and dieckol (50 ${\mu}g$/mL) significantly inhibited 3-hydroxyl-methyl glutaryl coenzyme A (HMGCoA) reductase activity in vitro. Taken together, these results suggest that polyphenols of Ecklonia cava (SPN) and dieckol reduce body weight gain and fat accumulation in HFD-induced obese mice, and that their hypolipidemic effect is related to the inhibition of adipogenesis of adipocytes and HMGCoA reductase activity.
The Effect of Whole Body Vibration Exercise on Ankle Joint Spasticity Patients with Chronic Stroke
( Yeo-reum Jo ),( Mo-beom Jeong ),( Dong-woo Lee ) 대한물리치료학회 2018 대한물리치료학회지 Vol.30 No.4
Purpose: This study aimed to determine the appropriate stimulus strength that could result in a positive effect on the ankle joint spasticity when patients with chronic stroke performed whole body vibration (WBV) exercise. Methods: Among 72 patients who were diagnosed with stroke at least 6 months ago, those able to perform a half squat pose with ambulation issues due to ankle joint spasticity (modified Ashworth scale, MAS≥2) were included for analysis. Individuals participated in four different frequencies of vertical WBV exercise; 0 Hz, 10 Hz, 20 Hz, and 30 Hz. Vibration amplitude was 3-4 mm and 5 minutes WBV exercise was performed at each frequency, followed by a measurement after 2-minute rest. We assigned 18 individuals to each frequency and asked them to participate in the WBV exercise once every 3 weeks. The level of spasticity was evaluated by visual analogue scale (VAS) for self-assessment. The myoton PRO was utilized to objectively evaluate the level of spasticity and check the muscle tone and stiffness. Results: Participants showed 0 Hz VAS was a significant difference between 20 Hz application conditions (p<0.05). Muscle tone was significantly different at 0 Hz between 20 Hz, and 30 Hz (p<0.05), significantly difference at 10 Hz between 30 Hz (p<0.05). Muscle stiffness significantly difference at 0 Hz between 20 Hz, and 30 Hz (p<0.05), significantly difference at 10 Hz between 20 Hz, and 30 Hz (p<0.05). Conclusion: Findings of this study show that the frequency of more than 20 Hz was effective in improving the ambulatory ability in patients with chronic stroke. Currently, the effective WBV protocol is limited. Hence, this study was designed to suggest an effective WBV protocol to improve neuromodulation ability for chronic stroke patients.