Stimulatory heterotrimeric GTP‐binding protein augments cisplatin‐induced apoptosis by upregulating Bak expression in human lung cancer cells

Oh, Jung Min; Kim, So Young; Seo, Min Ji; Juhnn, Yong Sung

doi:10.1111/j.1349-7006.2009.01136.x

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…We previously reported that the cAMP signaling system regulated lung cancer cell apoptosis through various mechanisms (that is, by modulating the expression of Bcl-2 family proteins 35, 36 and by regulating ataxia-telangiectasia-mutated (ATM) activation in lung cancer cells 37 ). Here, we introduce the repression of TIPRL expression by a HDAC8 expression increase as a novel mechanism by which cAMP signaling modulates apoptosis.…”

Section: Discussionmentioning

confidence: 99%

cAMP signaling increases histone deacetylase 8 expression via the Epac2–Rap1A–Akt pathway in H1299 lung cancer cells

Park

Juhnn

2017

Exp Mol Med

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This study was performed to investigate the signaling pathway that mediates cyclic AMP (cAMP)-induced inhibition of histone deacetylase 8 (HDAC8) degradation, and the effect and underlying mechanisms of the resulting increase in HDAC8 expression on cisplatin-induced apoptosis in lung cancer cells. cAMP signaling increased HDAC8 expression via a protein kinase A (PKA)-independent pathway in H1299 non-small cell lung cancer cells. However, treatment with a selective activator of an exchange protein that was activated by cAMP (Epac) increased HDAC8 expression, and Epac2 inhibition abolished the isoproterenol (ISO)-induced increase in HDAC8 expression. ISO and the Epac activator activated Rap1, and Rap1A activation increased HDAC8 expression; moreover, inhibition of Rap1A with a dominant negative Rap1A or by shRNA-mediated knockdown abolished the ISO-induced increase in HDAC8 expression. Activation of cAMP signaling and Rap1A decreased the activating phosphorylation of Akt. Akt inhibition with a pharmacological inhibitor or expression of a dominant negative Akt inhibited the MKK4/JNK pathway and increased HDAC8 expression. The Akt inhibitor-induced increase in HDAC8 expression was abolished by pretreatment with proteasomal or lysosomal inhibitors. The ISO treatment increased cisplatin-induced apoptosis, which was abolished by HDAC8 knockdown. Exogenous HDAC8 expression increased cisplatin-induced apoptosis and decreased TIPRL expression, and the knockdown of TIPRL increased the apoptosis of cisplatin-treated cells. The ISO treatment decreased cisplatin-induced transcription of the TIPRL gene in a HDAC8-dependent manner. In conclusion, the Epac–Rap1–Akt pathway mediates cAMP signaling-induced inhibition of JNK-dependent HDAC8 degradation, and the resulting HDAC8 increase augments cisplatin-induced apoptosis by repressing TIPRL expression in H1299 lung cancer cells.

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Section: Discussionmentioning

confidence: 99%

cAMP signaling increases histone deacetylase 8 expression via the Epac2–Rap1A–Akt pathway in H1299 lung cancer cells

Park

Juhnn

2017

Exp Mol Med

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“…Choi, et al show that the expression of constitutively activated Gα s in the A549 and H1299 human lung cancer cell lines augments cisplatin induced apoptosis through the modulation of Bcl-2 family proteins, specifically the up regulation of BAX and BAK and the down regulation of Bcl-2 and Bcl-xL [120]. Conversely, Seo, et al .…”

Section: Note: Added In Proofmentioning

confidence: 99%

Heterotrimeric G Proteins and Apoptosis: Intersecting Signaling Pathways Leading to Context Dependent Phenotypes

Yanamadala¹,

Negoro²,

Denker³

2009

CMM

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Apoptosis, a programmed cell death mechanism, is a fundamental process during the normal development and somatic maintenance of all multicellular organisms and thus is highly conserved and tightly regulated through numerous signaling pathways. Apoptosis is of particular clinical importance as its dysregulation contributes significantly to numerous human diseases, primarily through changes in the expression and activation of key apoptotic regulators. Each of the four families of heterotrimeric G proteins (Gs, Gi/o, Gq/11 and G12/13) has been implicated in numerous cellular signaling processes, including proliferation, transformation, migration, differentiation, and apoptosis. Heterotrimeric G protein signaling is an important but not widely studied mechanism regulating apoptosis. G protein Signaling and Apoptosis broadly cover two large bodies of literature and share numerous signaling pathways. Examination of the intersection between these two areas is the focus of this review. Several studies have implicated signaling through each of the four heterotrimeric G protein families to regulate apoptosis within numerous disease contexts, but the mechanism(s) are not well defined. Each G protein family has been shown to stimulate and/or inhibit apoptosis in a context-dependent fashion through regulating numerous downstream effectors including the Bcl-2 family, NF-κB, PI3 Kinase, MAP Kinases, and small GTPases. These cell-type specific and G protein coupled receptor dependent effects have led to a complex body of literature of G protein regulation of apoptosis. Here, we review the literature and summarize apoptotic signaling through each of the four heterotrimeric G protein families (and the relevant G protein coupled receptors), and discuss limitations and future directions for research on regulating apoptosis through G protein coupled mechanisms. Continued investigation in this field is essential for the identification of important targets for pharmacological intervention in numerous diseases.

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“…This in turn regulates the expression of other genes (6). cAMP signaling also modulates cancer cell death induced by anticancer drugs and ␥-rays (7,8).…”

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confidence: 99%

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

Kim

Juhnn

2015

Journal of Biological Chemistry

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Background: cAMP signaling augments radiation-induced apoptosis of lung cancer cells. Results: cAMP signaling reduces the expression of sirtuin 6 deacetylase in non-small cell lung cancer cells by promoting ubiquitin-proteasomal degradation via inhibition of the Raf-MEK-ERK pathway. Conclusion: cAMP signaling reduces sirtuin 6, which augments radiation-induced apoptosis in lung cancer cells. Significance: cAMP signaling augments radiation-induced apoptosis by modulating epigenetic control.

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Stimulatory heterotrimeric GTP‐binding protein augments cisplatin‐induced apoptosis by upregulating Bak expression in human lung cancer cells

Cited by 8 publications

References 26 publications

cAMP signaling increases histone deacetylase 8 expression via the Epac2–Rap1A–Akt pathway in H1299 lung cancer cells

cAMP signaling increases histone deacetylase 8 expression via the Epac2–Rap1A–Akt pathway in H1299 lung cancer cells

Heterotrimeric G Proteins and Apoptosis: Intersecting Signaling Pathways Leading to Context Dependent Phenotypes

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

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