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An increase in galectin-3 causes cellular unresponsiveness to IFN-?-induced signal transduction and growth inhibition in gastric cancer cells.

ABSTRACT: Glycogen synthase kinase (GSK)-3? facilitates interferon (IFN)-? signaling by inhibiting Src homology-2 domain-containing phosphatase (SHP) 2. Mutated phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) cause AKT activation and GSK-3? inactivation to induce SHP2-activated cellular unresponsiveness to IFN-? in human gastric cancer AGS cells. This study investigated the potential role of galectin-3, which acts upstream of AKT/GSK-3?/SHP2, in gastric cancer cells. Increasing or decreasing galectin-3 altered IFN-? signaling. Following cisplatin-induced galectin-3 upregulation, surviving cells showed cellular unresponsiveness to IFN-?. Galectin-3 induced IFN-? resistance independent of its extracellular ?-galactoside-binding activity. Galectin-3 expression was not regulated by PI3K activation or by a decrease in PTEN. Increased galectin-3 may cause GSK-3? inactivation and SHP2 activation by promoting PDK1-induced AKT phosphorylation at a threonine residue. Overexpression of AKT, inactive GSK-3?R96A, SHP2, or active SHP2D61A caused cellular unresponsiveness to IFN-? in IFN-?-sensitive MKN45 cells. IFN-?-induced growth inhibition and apoptosis in AGS cells were observed until galectin-3 expression was downregulated. These results demonstrate that an increase in galectin-3 facilitates AKT/GSK-3?/SHP2 signaling, causing cellular unresponsiveness to IFN-?.

SUBMITTER: Tseng PC

PROVIDER: S-EPMC4924776 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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An increase in galectin-3 causes cellular unresponsiveness to IFN-γ-induced signal transduction and growth inhibition in gastric cancer cells.

Tseng Po-Chun PC Chen Chia-Ling CL Shan Yan-Shen YS Lin Chiou-Feng CF

Oncotarget 20160301 12

Glycogen synthase kinase (GSK)-3β facilitates interferon (IFN)-γ signaling by inhibiting Src homology-2 domain-containing phosphatase (SHP) 2. Mutated phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) cause AKT activation and GSK-3β inactivation to induce SHP2-activated cellular unresponsiveness to IFN-γ in human gastric cancer AGS cells. This study investigated the potential role of galectin-3, which acts upstream of AKT/GSK-3β/SHP2, in gastric cancer cells. Increasing ...[more]

PMID: 26934444

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Project description:BACKGROUND: Spatial signal transduction plays a vital role in many intracellular processes such as eukaryotic chemotaxis, polarity generation and cell division. Furthermore it is being increasingly realized that the spatial dimension to signalling may play an important role in other apparently purely temporal signal transduction processes. It is increasingly being recognized that a conceptual basis for studying spatial signal transduction in signalling networks is necessary. RESULTS: In this work we examine spatial signal transduction in a series of standard motifs/networks. These networks include coherent and incoherent feedforward, positive and negative feedback, cyclic motifs, monostable switches, bistable switches and negative feedback oscillators. In all these cases, the driving signal has spatial variation. For each network we consider two cases, one where all elements are essentially non-diffusible, and the other where one of the network elements may be highly diffusible. A careful analysis of steady state signal transduction provides many insights into the behaviour of all these modules. While in the non-diffusible case for the most part, spatial signalling reflects the temporal signalling behaviour, in the diffusible cases, we see significant differences between spatial and temporal signalling characteristics. Our results demonstrate that the presence of diffusible elements in the networks provides important constraints and capabilities for signalling. CONCLUSIONS: Our results provide a systematic basis for understanding spatial signalling in networks and the role of diffusible elements therein. This provides many insights into the signal transduction capabilities and constraints in such networks and suggests ways in which cellular signalling and information processing is organized to conform to or bypass those constraints. It also provides a framework for starting to understand the organization and regulation of spatial signal transduction in individual processes.

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Dataset Information

An increase in galectin-3 causes cellular unresponsiveness to IFN-?-induced signal transduction and growth inhibition in gastric cancer cells.

Publications

An increase in galectin-3 causes cellular unresponsiveness to IFN-γ-induced signal transduction and growth inhibition in gastric cancer cells.

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