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- 저자 : Dmytro Starenki (검색결과 2 건)
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Dmytro Starenki,박종인 대한내분비학회 2015 Endocrinology and metabolism Vol.30 No.4
Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the rearranged during transfection (RET) proto-oncogene. Not all patients with progressive MTC respond to current therapy inhibiting RET, demanding additional therapeutic strategies. We recently demonstrated that disrupting mitochondrial metabolism using a mitochondria-targeted agent or by depleting a mitochondrial chaperone effectively suppressed human MTC cells in culture and in mouse xenografts by inducing apoptosis and RET downregulation. These observations led us to hypothesize that mitochondria are potential therapeutic targets for MTC. This study further tests this hypothesis using 1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-oxothiazolidin-2-ylidenemethyl] pyridinium chloride (MKT-077), a water-soluble rhodocyanine dye analogue, which can selectively accumulate in mitochondria. Methods: The effects of MKT-077 on cell proliferation, survival, expression of RET and tumor protein 53 (TP53), and mitochondrial activity were determined in the human MTC lines in culture and in mouse xenografts. Results: MKT-077 induced cell cycle arrest in TT and MZ-CRC-1. Intriguingly, MKT-077 also induced RET downregulation and strong cell death responses in TT cells, but not in MZ-CRC-1 cells. This discrepancy was mainly due to the difference between the capacities of these cell lines to retain MKT-077 in mitochondria. The cytotoxicity of MKT-077 in TT cells was mainly attributed to oxidative stress while being independent of TP53. MKT-077 also effectively suppressed tumor growth of TT xenografts. Conclusion: MKT-077 can suppress cell survival of certain MTC subtypes by accumulating in mitochondria and interfering with mitochondrial activity although it can also suppress cell proliferation via other mechanisms. These results consistently support the hypothesis that mitochondrial targeting has therapeutic potential for MTC.
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Kinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines
Nadiya Sosonkina,박종인,홍승근,Dmytro Starenki 한국유전학회 2014 Genes & Genomics Vol.36 No.6
Neuroendocrine (NE) lung tumors comprise20–25 % of all invasive lung malignancies. Currently, noeffective treatments are available to cure these tumors, andit is necessary to identify a molecular alteration(s) thatcharacterizes NE lung tumor cells. We aimed to identify akinase mutation(s) associated with NE lung tumor byscreening 517 kinase-encoding genes in human lung cancercell lines. Our next-generation sequencing analysis of sixNE lung tumor cell lines (four small cell lung cancer linesand two non-small cell lung cancer lines) and three non-NElung tumor lines revealed various kinase mutations,including a nonsynonymous mutation in the proto-oncogeneRET (c.2071G[A; p.G691S). Further evaluation ofthe RET polymorphism in total 15 lung cancer cell lines bycapillary sequencing suggested that the frequency of theminor allele (A-allele) in NE lung tumor lines was significantlyhigher than its frequency in a reference population(p = 0.0001). However, no significant difference betweennon-NE lung tumor lines and a reference group wasdetected (p = 1.0). Nevertheless, neither RET expressionlevels were correlated with the levels of neuron-specificenolase (NSE), a key NE marker, nor vandetanib andcabozantinib, small molecule compounds that inhibit RET,affected NSE levels in lung cancer cells. Our data suggest apotential association of G691S RET polymorphism withNE lung tumor, proposing the necessity of more thoroughevaluation of this possibility. The dataset of kinasemutation profiles in this report may help choosing cell linemodels for study of lung cancer.
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