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The Fluoro-Thiazolylhydrazone Compound TSC-3C Inhibits Triple Negative Breast Cancer (TNBC) Cell Line Activity by Promoting Apoptosis, Regulating the MAPK Pathway and Inducing Mitochondrial Dysfunction.
Zhang, J, Dai, J, Zheng, Q, Guo, S, Yu, Y, Hu, W, Gao, Y, Shi, D
International journal of molecular sciences. 2020;(3)
Abstract
Triple negative breast cancer (TNBC) is the most aggressive cancer in women, and despite improved treatments, it remains a major cause of morbidity and mortality. We and others have demonstrated that different hybrid compounds targeting PARP/MAPK or other pathways to inhibit cancer progression may lead to promising therapeutic results. We introduced fluorine to alter the physical properties of the compounds. TSC-3C was one of the generated compounds. Upon treatment with TSC-3C, MDA-MB-231 cell proliferation, invasion, and migration were inhibited. TSC-3C induced MDA-MB-231 cell mitochondrial dysfunction and apoptosis, which may be caused by reducing the level of phosphorylated p44/42 MAPK (ERK1/2) and increasing the level of p-JNK. The present study may help to elucidate the role of the MAPK pathway in the development of breast cancer and may promote further research on halogenated heterocyclic compounds for the treatment of breast cancer.
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The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters.
Alessi, DR, Zhang, J, Khanna, A, Hochdörfer, T, Shang, Y, Kahle, KT
Science signaling. 2014;(334):re3
Abstract
The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress-responsive kinase 1). The WNK family senses changes in intracellular Cl(-) concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na(+)), potassium (K(+)), and chloride (Cl(-)) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl(-)-importing, Na(+)-driven CCCs or inhibit the Cl(-)-extruding, K(+)-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK-SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K(+) secretion to lower blood pressure while maintaining serum K(+). In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl(-) extrusion and promote γ-aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K(+)-sparing blood pressure-lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism.
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Construction of human activity-based phosphorylation networks.
Newman, RH, Hu, J, Rho, HS, Xie, Z, Woodard, C, Neiswinger, J, Cooper, C, Shirley, M, Clark, HM, Hu, S, et al
Molecular systems biology. 2013;:655
Abstract
The landscape of human phosphorylation networks has not been systematically explored, representing vast, unchartered territories within cellular signaling networks. Although a large number of in vivo phosphorylated residues have been identified by mass spectrometry (MS)-based approaches, assigning the upstream kinases to these residues requires biochemical analysis of kinase-substrate relationships (KSRs). Here, we developed a new strategy, called CEASAR, based on functional protein microarrays and bioinformatics to experimentally identify substrates for 289 unique kinases, resulting in 3656 high-quality KSRs. We then generated consensus phosphorylation motifs for each of the kinases and integrated this information, along with information about in vivo phosphorylation sites determined by MS, to construct a high-resolution map of phosphorylation networks that connects 230 kinases to 2591 in vivo phosphorylation sites in 652 substrates. The value of this data set is demonstrated through the discovery of a new role for PKA downstream of Btk (Bruton's tyrosine kinase) during B-cell receptor signaling. Overall, these studies provide global insights into kinase-mediated signaling pathways and promise to advance our understanding of cellular signaling processes in humans.
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4.
Statins, autophagy and cancer metastasis.
Zhang, J, Yang, Z, Xie, L, Xu, L, Xu, D, Liu, X
The international journal of biochemistry & cell biology. 2013;(3):745-52
Abstract
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. They are traditionally considered to be cholesterol-lowering agents, but in recent years more and more effects of statins have been revealed, including anti-inflammation, immunomodulation, neuroprotection, improvement of bone metabolism, and antitumour effects. In the past few years, extensive studies have shown that statins can induce autophagy in tumour cells as well as in some normal cells, and autophagy may be involved in the regulation of cancer metastasis. This review is focused on summarising and discussing the relationships among statins, autophagy and cancer metastasis. Studies showed that activation of the AMPK-TOR signalling pathway may be a major mechanism of statin-induced autophagy. Depleting cellular geranylgeranyl diphosphate activates AMPK and inactivates TOR, leading to autophagic responses. Autophagy, a strategy of self-adaption, is a double-edged sword in tumour metastasis. On one hand, autophagy contributes to anti-metastasis activity by, for example, restricting tumour necrosis and inflammatory cell infiltration of tumours and promoting the release of high-mobility group box protein 1 that triggers strong antitumour immune responses. On the other hand, it also exhibits a pro-metastasis activity. In summary, we propose a working hypothesis: statins induce autophagy in cancer cells, and this constitutes, at least in part, the basis for the anti-metastatic effect of statins. The idea that autophagy is responsible for statin-induced anti-metastasis effects is probably novel, and it extends the conventional view that interference of the post-translational modification of Rho GTPases by statins prevents tumour metastasis.