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Hyperactivated m-calpain affects acquisition of doxorubicin resistance in breast cancer cells
Jeon, Kyung-Hwa,Yu, Han Vit,Kwon, Youngjoo Elsevier 2018 Biochimica et biophysica acta, General subjects Vol.1862 No.5
<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Doxorubicin is commonly using chemotherapeutic agents for breast cancer. However, doxorubicin has limitations in clinical use because of dose-dependent cardiotoxicity and drug resistance. Despite of previously reported studies about mechanisms of doxorubicin resistance including overexpression of P-gp and abnormal expression and mutation of topoisomerase IIα, resistance to this agent still abundantly occur and is regarded as a major obstacle to successful treatment.</P> <P><B>Methods</B></P> <P>We have established doxorubicin resistant T47D cells. Intracellular calcium and ROS levels and calpain activity were measured using fluorometric experiments. Cell viability assay, cell cycle analysis, immunofluorescence and western blot analysis were performed to evaluate m-calpain specific truncation of topoisomerase IIα and molecular mechanism in doxorubicin resistant cells.</P> <P><B>Results</B></P> <P>We observed that doxorubicin treatment increased intracellular calcium and ROS (Reactive Oxygen Species) in parental and doxorubicin resistant T47D cells. The increases in intracellular calcium and ROS were much greater in doxorubicin resistant T47D cells, which led to higher activity of calpains. Hyperactivated m-calpain, but not μ-calpain, specifically induced cleavage of topoisomerase IIα and accumulation of truncated topoisomerase IIα in the cytoplasm. The increase in cytoplasmic truncated topoisomerase IIα reduced the efficacy of doxorubicin. Doxorubicin resistant T47D cells, with hyperactivated m-calpain and truncated cytosolic topoisomerase IIα, obtained cross-resistance to other topoisomerase II-targeting drugs.</P> <P><B>Conclusion</B></P> <P>Hyperactivated m-calpain induced cytoplasmic accumulation of truncated topoisomerase IIα in doxorubicin resistant T47D cells.</P> <P><B>General significance</B></P> <P>These data provide a new mechanism of doxorubicin resistance and suggest a novel strategy for overcoming drug resistance in topoisomerase IIα-targeting therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Doxorubicin (DOX) treatment enhances calpain activity. </LI> <LI> DOX is accumulated in cytoplasm of doxorubicin resistant T47D cells (T47D<SUP>DOX/R</SUP>). </LI> <LI> T47D<SUP>DOX/R</SUP> cells represented cytoplasmic accumulation of truncated topoisomerase IIα. </LI> <LI> Cleavage of topoisomerase IIα was diminished in m-calpain knock-downed cells. </LI> <LI> T47D<SUP>DOX/R</SUP> cells acquired cross-drug resistance. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Synthesis and topoisomerases inhibitory activity of heteroaromatic chalcones
Jeon, K.H.,Yu, H.B.,Kwak, S.Y.,Kwon, Y.,Na, Y. Elsevier/Pergamon 2016 Bioorganic & medicinal chemistry Vol.24 No.22
The critical role of nuclear topoisomerase enzymes during cell proliferation process guided topoisomerases to be one of the major targets for anticancer drug development. We have designed and synthesized 22 heteroaromatic ring incorporated chalcone derivatives substituted with epoxide or thioepoxide. Topoisomerase enzyme inhibitory activity and cytotoxic tests were also conducted to evaluate compounds' pharmacological efficacy. In the topoisomerase I inhibitory test, compound 1 was most active one, 24% of inhibition at 20μM, among all the compounds but it was lower than camptothecin. Compounds 9, 11, and 13 inhibited the function of topoisomerase II more strongly than etoposide with almost same magnitude (around 90% and 30% inhibition at 100 and 20μM, respectively) which were higher than those of etoposide (72% and 18% inhibition). In the cytotoxicity test, compound 9 inhibited T47D cancer cell growth with the IC<SUB>50</SUB> value of 6.61+/-0.21μM. On the other hand, compound 13 (IC<SUB>50</SUB>: 4.32+/-0.18μM) effectively suppressed MDA-MB468 cancer cell growth.
Coherent control of 171Yb+ ion qubit states and thermometry using motional decoherence
Jeon Honggi,Park Nojun,Yu Jiyong,Kwon Yeong-Dae,염다현,Jhe Wonho 한국물리학회 2021 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.78 No.4
171Yb+ions were trapped in a quadrupole ion trap. A mode-locked pulse laser at 355 nm was used to generate a frequency comb to drive a Raman transition between the ground hyperfine qubit states of the Doppler cooled ion. Qubit transitions were driven in co-propagating and counter propagating laser beam geometries. In the co-propagating geometry, the coherence time and the fidelity of gate operations were obtained. By taking advantage of the phonon number sensitivity of the Rabi frequency in the counter-propagating geometry, we measured the center of mass temperature of the trapped ion near the Doppler limit which can be used for general thermometry in the ion trap experiment.
Hydrodeoxygenation of Guaiacol Over Pt/Al-SBA-15 Catalysts.
Yu, Mi Jin,Park, Sung Hoon,Jeon, Jong-Ki,Ryu, Changkook,Sohn, Jung Min,Kim, Sang Chai,Park, Young-Kwon American Scientific Publishers 2015 Journal of Nanoscience and Nanotechnology Vol.15 No.1
<P>Upgrading of bio-oil through catalytic hydrodeoxygenation (HDO) reaction was investigated for guaiacol as a model compound. A batch reactor was used for the reaction condition of 40 bar and 250 degrees C. The target product was cyclohexane. Pt/Al-SBA-15 with the Si/Al ratios of 20, 40, and 80 and Pt/HZSM-5 were used as the catalyst. The SBA-15 catalysts were characterized by N2 adsorption-desorption, X-ray diffraction analysis, and temperature programmed desorption of ammonia. The order of cyclohexane yield was Pt/Al-SBA-15 (Si/Al = 20) > Pt/Al-SBA-15(40) > Pt/Al-SBA-15 (80), indicating that the quantity of acid sites plays an important role in the HDO reaction. On the other hand, Pt/HZSM-5 led to a very low cyclohexane yield, in spite of its abundant strong acid sites, due to its small pore size.</P>
Jeon, Yu-Mi,Lee, Shinrye,Kim, Seyeon,Kwon, Younghwi,Kim, Kiyoung,Chung, Chang Geon,Lee, Seongsoo,Lee, Sung Bae,Kim, Hyung-Jun Korean Society for Molecular and Cellular Biology 2017 Molecules and cells Vol.40 No.4
Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers ($eIF2{\alpha}$ phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases.