Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways

Lai, Yi-Hua; Chen, Min-Hsuan; Lin, Sih-Yin; Lin, Shengrong; Wong, Yuen Yee; Yu, Sung‐Liang; Chen, Huei‐Wen; Yang, Chih-Hsin; Chang, Gee‐Chen; Chen, Jeremy J.W.

doi:10.18632/oncotarget.4761

Cited by 10 publications

(12 citation statements)

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“…The first step in metastasis is the migration of cancer cells away from the primary tumor, a process called tumor invasion 20 . Therefore, much research effortin recent years has been directed toward disruption of this step of the metastatic process 21 22 . In this study, we chose MDA-MB-231 cells with high metastatic potential to explore the effects of metapristone on the metastatic activity of human breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention

Yan

Yang

et al. 2016

Sci Rep

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Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent by us. Despite its prominent metastasis chemopreventive effect, the underlying mechanism remains elusive. Our study, for the first time, demonstrated that metapristone had the ability to prevent breast cancer cells from migration, invasion, and interfere with their adhesion to endothelial cells. To explore the underlying mechanism of metapristone, we employed the iTRAQ technique to assess the effect of metapristone on MDA-MB-231 cells. In total, 5,145 proteins were identified, of which, 311 proteins showed significant differences in metapristone-treated cells compared to the control group (P-value < 0.05). Bioinformatic analysis showed many differentially expressed proteins (DEPs) functionally associated with post-translational modification, chaperones, translation, transcription, replication, signal transduction, etc. Importantly, many of the DEPs, such as E-cadherin, vimentin, TGF-β receptor I/II, smad2/3, β-catenin, caveolin, and dystroglycan were associated with TGF-β and Wnt signaling pathways, which were also linked to epithelial-to-mesenchymal transition (EMT) process. Further validation of the epithelial marker “E-caderin” and mesenchymal marker “vimetin” were carried out using immunoblot and immunofluorescence. These results have revealed a novel mechanism that metapristone-mediated metastasis chemoprevention is through intervening the EMT-related signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention

Yan

Yang

et al. 2016

Sci Rep

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“…Colonies with a diameter greater than 0.2 mm were counted using an inverted microscope. Details regarding the methods used to perform this procedure are provided elsewhere [ 19 ].…”

Section: Methodsmentioning

confidence: 99%

“…Tumors were induced in nude mice according to a previously described protocol [ 19 ]. Five-week-old severe combined immunodeficiency (SCID) nude mice were purchased from the National Laboratory Animal Center (NLAC, Taipei, Taiwan).…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown that Src kinase inhibitors can induce NSCLC cell apoptosis and inhibit angiogenesis and, depending on the EGFR mutation status, EGFR tyrosine kinase activation [ 17 , 18 ]. Furthermore, a previous study showed that combination therapy with Src inhibitors and gefitinib can enhance the effects of TKIs on EGFR and STAT3 [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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AC-93253 iodide, a novel Src inhibitor, suppresses NSCLC progression by modulating multiple Src-related signaling pathways

Lai

Lin

et al. 2017

J Hematol Oncol

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BackgroundThe tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds.MethodsHuman non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment. Src and Src-related protein expression in AC-93253 iodide-treated PC9, PC9/gef, and A549 cells were assessed by western blotting. The effects of AC-93253 iodide on cancer cell colony formation, invasion, and migration were assessed in PC9 and PC9/gef cells. The synergistic effects of gefitinib and AC-93253 iodide were evaluated by combination index (CI)-isobologram analysis in gefitinib-resistant cell lines. The efficacy of AC-93253 iodide in vivo was determined using nude mice treated with either the compound or the vehicle.ResultsAmong the compounds, AC-93253 iodide exhibited the most potent dose-independent inhibitory effects on the activity of Src as well as on that of the Src-related proteins EGFR, STAT3, and FAK. Furthermore, AC-93253 iodide significantly suppressed cancer cell proliferation, colony formation, invasion, and migration in vitro and tumor growth in vivo. AC-93253 iodide sensitized tumor cells to gefitinib treatment regardless of whether the cells were gefitinib-sensitive (PC9) or resistant (H1975 and PC9/gef), indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our findings also suggested that the inhibitory effects of AC-93253 iodide on lung cancer progression may be attributable to its ability to modulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, MEK, ERK, and EGFR.ConclusionsOur data suggest that AC-93253 iodide inhibits NSCLC cell growth and motility by regulating multiple Src-related pathways. Our findings may facilitate the development of therapeutic strategies and anti-tumor drugs that may be useful for treating lung cancer in the future.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0539-3) contains supplementary material, which is available to authorized users.

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“…The redoxactivation of SFKs can induce sustained PI3K, protein kinase C (PKC), and extracellular regulated kinase (ERK) activation and, thereby, create conditions for tumor cell growth, invasion, angiogenesis, and resistance to apoptosis [126]. In a variety of human cancers an increased activity of Src kinases have been described, as well as activation of important Src downstream targets such as PI3K/Akt, focal adhesion kinase (FAK), paxillin, p130Cas, signal transducer and activator of transcription 3 (STAT3) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) [127][128][129][130].…”

Section: Some Ros Such As Omentioning

confidence: 99%

Oxidative Stress: Noxious but Also Vital

Bagatini¹,

Jaques²,

Oliveira³

et al. 2018

Novel Prospects in Oxidative and Nitrosative Stress

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The imbalance between reactive oxygen species (ROS) production and antioxidant defenses determines the condition called oxidative stress. When there is an increase in ROS production or a decrease in the antioxidant defenses, this systemic antioxidant/pro-oxidant imbalance may lead to the accumulation of oxidative damage, which, in turn, may lead to a modification of biomolecules. These consist of reactions resulting in protein adducts, DNA oxidation, and formation of lipid peroxides, which, in turn, reduce the cellular functional capacity and increase the risk of disease development. The body has natural scavenging systems against free radicals and other reactive species. However, sometimes the endogenous antioxidant capacity is exceeded by the production of ROS. When this occurs, exogenous antioxidants exert important function for the human health. These bioactive compounds act preventing and neutralizing the formation of new reactive species and free radical s .I ns o m ec a s e s ,a n increase of ROS can help the host to resolve an infection or even to control the tumor growth. Finally, the levels of ROS can be perceived by signal transduction pathways involving known targets(i.e.,p53,Ras,andNF-κB) and regulate physiopathological events such as the cellular cycle, apoptosis, and inflammation.Keywords: reactive species, cellular oxidation, antioxidant system, health, disease © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cellular respiration and generation of reactive species in the mitochondria: implications in cell viability and agingOxidative phosphorylation is the center of energy metabolism in plants, animals and several microbial life forms [1]. In eukaryotes, this process occurs in mitochondria. The mitochondria is a cytoplasmic organelle surrounded by two membranes, outer and inner membrane, which main function is the production of most of the phosphate compounds necessary for the energetic balance of the cell. In addition, other functions such as the regulation of the body'sheatgeneration [2][3][4] programmed cell death [5][6][7], reactive oxygen species (ROS) generation and cell signaling [8] is also associated with mitochondria. Cellular vitality is directly related to mitochondria, and mitochondrial dysfunctions are frequent causes of accidental cell death [5,[9][10][11], cancer [12, 13], diabetes [14][15][16] and neurodegenerative diseases [17][18][19], among others.The characterization of the respiratory electron chain could be performed in studies using the fractionation of its components by certain detergents that at low concentrations break the interactions between proteins and lipids in the membranes, leaving associations between proteins intact [20]. In electron transport chain, through this process, four protein complexes were found....

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Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways

Cited by 10 publications

References 50 publications

Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention

Pharmacoproteomic analysis reveals that metapristone (RU486 metabolite) intervenes E-cadherin and vimentin to realize cancer metastasis chemoprevention

AC-93253 iodide, a novel Src inhibitor, suppresses NSCLC progression by modulating multiple Src-related signaling pathways

Oxidative Stress: Noxious but Also Vital

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