PI3K/Akt and GSK-3β prevents in a differential fashion the malignant phenotype of colorectal cancer cells

Araújo, Wallace Martins de; Vidal, Flavia Castello Branco; Souza, Waldemir Fernandes de; de-Freitas-Junior, Júlio Cesar Madureira; Souza, Wanderley de; Morgado‐Díaz, José Andrés

doi:10.1007/s00432-010-0836-5

Cited by 21 publications

(18 citation statements)

References 33 publications

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“…GSK-3 β , known to be a survival factor for cancer, is constitutively activated in colorectal cancer cells. Deregulation of GSK-3 β has been implicated in tumorigenesis and cancer progression including that of colorectal cancer [15]. LiCl has been shown to induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors by targeting GSK-3 β [16].…”

Section: Discussionmentioning

confidence: 99%

Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway

Huang

Liu

et al. 2014

Oxidative Medicine and Cellular Longevity

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Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, has been regarded as a potential therapeutic target for multiple human cancers. In addition, oxidative stress is closely related to all aspects of cancer. We sought to determine the biological function of lithium, one kind of GSK-3β inhibitors, in the process of reactive oxygen species (ROS) production in colorectal cancer. In this study, we analyzed the cell apoptosis and proliferation by cell viability, EdU, and flow cytometry assays through administration of LiCl. We used polymerase chain reaction and Western blotting to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Results showed administration of LiCl increased apoptosis and the level of ROS in colorectal cancer cells. Furthermore, the underlying mechanisms could be mediated by the reduction of NF-κB expression and NF-κB-mediated transcription. Taken together, our results demonstrated that therapeutic targeting of ROS/GSK-3β/NF-κB pathways may be an effective way for colorectal cancer intervention, although further preclinical and clinical testing are desirable.

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Section: Discussionmentioning

confidence: 99%

Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway

Huang

Liu

et al. 2014

Oxidative Medicine and Cellular Longevity

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“…The epidermal growth factor receptor (EGFR) is dimerized and activated by its extracellular ligand, EGF, which triggers a signaling cascade that leads to the activation of cytoplasmic pathways such as MAPK and PI3K-Akt [7], [8]; these pathways are known to modulate proliferation, differentiation and resistance to cell death [9], [10]. Studies have shown that these pathways are involved in events related to the carcinogenic processes in mouse epidermal and human gastric cancer cells [11], [12], as well as in the increased migratory and invasive potential during the epithelial-mesenchymal transition in human ovarian cells [13].…”

Section: Introductionmentioning

confidence: 99%

Claudin-3 Overexpression Increases the Malignant Potential of Colorectal Cancer Cells: Roles of ERK1/2 and PI3K-Akt as Modulators of EGFR signaling

et al. 2013

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The altered expressions of claudin proteins have been reported during the tumorigenesis of colorectal cancer. However, the molecular mechanisms that regulate these events in this cancer type are poorly understood. Here, we report that epidermal growth factor (EGF) increases the expression of claudin-3 in human colorectal adenocarcinoma HT-29 cells. This increase was related to increased cell migration and the formation of anchorage-dependent and anchorage-independent colonies. We further showed that the ERK1/2 and PI3K-Akt pathways were involved in the regulation of these effects because specific pharmacological inhibition blocked these events. Genetic manipulation of claudin-1 and claudin-3 in HT-29 cells showed that the overexpression of claudin-1 resulted in decreased cell migration; however, migration was not altered in cells that overexpressed claudin-3. Furthermore, the overexpression of claudin-3, but not that of claudin-1, increased the tight junction-related paracellular flux of macromolecules. Additionally, an increased formation of anchorage-dependent and anchorage-independent colonies were observed in cells that overexpressed claudin-3, while no such changes were observed when claudin-1 was overexpressed. Finally, claudin-3 silencing alone despite induce increase proliferation, and the formation of anchoragedependent and -independent colonies, it was able to prevent the EGF-induced increased malignant potential. In conclusion, our results show a novel role for claudin-3 overexpression in promoting the malignant potential of colorectal cancer cells, which is potentially regulated by the EGF-activated ERK1/2 and PI3K-Akt pathways.

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“…Em trabalhos recentes, relatamos a participação das vias da PI3K/Akt, ERK1/2 e Rho GTPases regulando eventos da progressão deste tipo de câncer (17)(18)(19). Um resumo de nossos resultados está esquematizado na figura 2.…”

Section: Vias De Sinalização Celular Que Regulam a Progressão Dounclassified

Sinalização celular em câncer

et al. 2014

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o rganismos pluricelulares complexos (como os seres humanos) são constituídos por um conjunto de órgãos, formados por tecidos, os quais reúnem um conjunto de células especializadas para desempenharem funções específicas. O desenvolvimento desses organismos e a manutenção de suas funções vitais dependem de uma cooperação das células que os constituem, na medida em que os processos realizados por essas células têm que ser desempenhados de maneira coordenada. Para que isso ocorra, as células necessitam se comunicar umas com as outras e, a partir desta comunicação, coordenar as funções desempenhadas por cada tipo celular. Esse é o princípio da sinalização celular, onde células se comunicam através de moléculas-sinal, secretadas ou expostas em sua superfície.As moléculas-sinal são reconhecidas por receptores, geralmente proteínas que podem estar expostas na superfície celular ou presentes no interior das células. Esses receptores, após se ligarem às molé-culas-sinal, transmitem a informação para outras proteínas presentes no interior da célula, mecanismo conhecido como transdução de sinal. Esse mecanismo pode desencadear diferentes respostas, como alteração da função de uma proteína (resposta rápida e passageira) ou modificação de expressão gênica, levando a uma alteração na quantidade de proteína dentro da célula (resposta lenta e mais prolongada). Essas modificações levam a alterações no comportamento da célula, visto que as proteínas são as responsáveis por dirigir as funções celulares (Figura 1).A transdução de sinal ocorre através de vias de sinalização, as quais geralmente são constituídas por proteínas comprometidas com a regulação de eventos da fisiologia celular, como proliferação, migração, diferenciação celular etc. A maior parte das proteínas que participam das vias de sinalização são enzimas, biocatalizadores que atuam na aceleração das reações bioquímicas que ocorrem dentro da célula. Dentre elas encontram-se as quinases, que constituem uma das principais famílias de proteínas em mamíferos. Elas são enzimas que catalisam a transferência de grupos fosfatos de moléculas do nucleotídeo adenosina trifosfato (ATP) para outras moléculas orgânicas, como lipídeos e proteínas. Como exemplo, podemos citar as quinases reguladas por sinal extracelular 1/2 (ERK1/2, Extracellular Signal-Regulated Kinase 1/2), proteínas serina/treonina quinase que atuam na fosforilação de aminoácidos serina e treonina presentes em seus alvos proteicos; e a fosfatidilinositol 3-quinase (PI3K, PhosphatidylInositide 3-Kinase), que atua na fosforilação do fosfolipídio fosfatidilinositol presente nas membranas celulares.Outras proteínas com grande participação em vias de sinalização são as que compreendem a família das GTPases, enzimas que quando ativas atuam na hidrólise da molécula do nucleotídeo guanosina trifosfato (GTP), gerando como produto guanosina difosfato (GDP) e fosfato inorgânico. As GTPases são enzimas que ciclam entre um estado ativo ligado à GTP e um estado inativo ligado à GDP, mecanismo controlado por proteínas regulatóri...

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PI3K/Akt and GSK-3β prevents in a differential fashion the malignant phenotype of colorectal cancer cells

Abstract: Our results demonstrate that PI3K/Akt and GSK-3β prevents in a differential fashion the malignant phenotype of HCT-116 colorectal cancer cells, which could constitute a potential therapeutic target for treatment of this cancer type.

Cited by 21 publications

References 33 publications

Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway

Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway

Claudin-3 Overexpression Increases the Malignant Potential of Colorectal Cancer Cells: Roles of ERK1/2 and PI3K-Akt as Modulators of EGFR signaling

Sinalização celular em câncer

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