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      A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A)

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          Abstract

          KP1019 ([trans-RuCl 4(1H-indazole) 2]; FFC14A) is one of the promising ruthenium-based anticancer drugs undergoing clinical trials. Despite the pre-clinical and clinical success of KP1019, the mode of action and various factors capable of modulating its effects are largely unknown. Here, we used transcriptomics and genetic screening approaches in budding yeast model and deciphered various genetic targets and plethora of cellular pathways including cellular signaling, metal homeostasis, vacuolar transport, and lipid homeostasis that are primarily targeted by KP1019. We also demonstrated that KP1019 modulates the effects of TOR (target of rapamycin) signaling pathway and induces accumulation of neutral lipids (lipid droplets) in both yeast and HeLa cells. Interestingly, KP1019-mediated effects were found augmented with metal ions (Al 3+/Ca 2+/Cd 2+/Cu 2+/Mn 2+/Na +/Zn 2+), and neutralized by Fe 2+, antioxidants, osmotic stabilizer, and ethanolamine. Additionally, our comprehensive screening of yeast histone H3/H4 mutant library revealed several histone residues that could significantly modulate the KP1019-induced toxicity. Altogether, our findings in both the yeast and HeLa cells provide molecular insights into mechanisms of action of KP1019 and various factors (chemical/genetic/epigenetic) that can alter the therapeutic efficiency of this clinically important anticancer drug.

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          Most cited references118

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            Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.

            CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.
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              Mitogen-activated protein kinases in apoptosis regulation.

              Cells are continuously exposed to a variety of environmental stresses and have to decide 'to be or not to be' depending on the types and strength of stress. Among the many signaling pathways that respond to stress, mitogen-activated protein kinase (MAPK) family members are crucial for the maintenance of cells. Three subfamilies of MAPKs have been identified: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38-MAPKs. It has been originally shown that ERKs are important for cell survival, whereas JNKs and p38-MAPKs were deemed stress responsive and thus involved in apoptosis. However, the regulation of apoptosis by MAPKs is more complex than initially thought and often controversial. In this review, we discuss MAPKs in apoptosis regulation with attention to mouse genetic models and critically point out the multiple roles of MAPKs.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                17 November 2017
                30 September 2017
                : 8
                : 58
                : 98426-98454
                Affiliations
                1 Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal 462066, India
                Author notes
                Correspondence to: Raghuvir Singh Tomar, rst@ 123456iiserb.ac.in
                Article
                21416
                10.18632/oncotarget.21416
                5716741
                eb10818b-ff3c-4923-bea9-403da421c30d
                Copyright: © 2017 Golla et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 27 April 2017
                : 28 August 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                anticancer,kp1019,histones,transcriptomics,metal homeostasis
                Oncology & Radiotherapy
                anticancer, kp1019, histones, transcriptomics, metal homeostasis

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