Gαs sensitizes human SH-SY5Y cells to apoptosis independently of the protein kinase A pathway

Zhao, Chunnian; Lai, Justin S.; Warsh, Jerry J.; Li, Peter P.

doi:10.1002/jnr.20875

Cited by 6 publications

(4 citation statements)

References 52 publications

(71 reference statements)

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“…Another possible explanation for the increased sensitivity of the SH-SY5Y line may be linked with the relatively high but consistent background apoptosis seen in the SH-SY5Y cells in this study compared to that of the SK-N-SH line in previous work [8]. A number of factors may influence the predisposition of different neuroblastoma lines to enter apoptosis, such as effects on protein kinase C, Bcl-2 and the long spliced variant of the G protein G1 s-L [14,15], as well as differential responses to growth factors [9].…”

Section: Discussionsupporting

confidence: 55%

A Comparison of the Apoptotic and Cytotoxic Effects of Hexanedione Derivatives on Human Non‐Neuronal Lines and the Neuroblastoma Line SH‐SY5Y

Coleman

Zilz

Griffiths

et al. 2007

Basic Clin Pharma Tox

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Abstract:The effects of the α-diketone derivatives 2,3-and 3,4-hexanediones were investigated in three non-neuronal cell lines (MCF7, HepG 2 and CaCo-2) as well as in the neuroblastoma line, SH-SY5Y. The MTT reduction assay was employed to determine the necrotic effects of the α-diketones and the neurotoxin 2,5-hexanedione over 4, 24 and 48 hr exposures. Flow cytometry was also used to study the effects of the three isomers on the cell cycle of the SH-SY5Y line only. With 2,5-hexanedione, the mean MTT IC 50 decreased more than 10-fold from 4 to 48 hr. The toxicities of both α-diketones were similar, with a more than 18-fold increase in sensitivity of the SH-SY5Y at 24 hr compared to that of 4 hr. With flow cytometry at 48 hr, SH-SY5Y apoptosis with 2,5-hexanedione rose throughout the concentration range evaluated (0-30 mM) while 2,3-and 3,4-hexanediones showed apoptosis over the concentration range 1-1.6 mM, with 3,4-hexanedione being the more potent compared to the 2,3-isomer. At 1.6 mM nearly all the cells had entered apoptosis in the presence of the 3,4-isomer, (94.9 ± 1.4%) but only 57.5 ± 4.1% of the 2,3-isomer-treated cells had reached that stage. The 2,3-and 3,4-isomers in diets alone may not pose a serious threat to human health. Further studies may be necessary to evaluate the effects of other dietary components on their toxicity. These α-diketones also display a degree of toxic selectivity towards neuroblastoma cells, which may have therapeutic implications.Hexanediones are formed biologically (2,5-hexanedione) as a result of exposure to the organic solvent hexane [1] and they also are present in the diet as food colourings and flavouring agents. 2,3-Hexanedione occurs naturally in beer, coffee and fermented soya beans and is used commercially to yield a buttery-cheesy taste in various foodstuffs and fragrances. 3,4-Hexanedione also occurs naturally in coffee, as well as cauliflower and it yields a sweet caramel-buttery odour and taste in butter, margarine and fruit flavourings [2]. The 2,5-isomer is an established human neurotoxin, which causes the cross-linking of neurofilaments; this process is linked to the onset of a polyneuropathy that is associated with occupational exposure to hexane [3,4]. In contrast, the 2,3-and 3,4-isomers have been generally viewed as non-toxic [2,5] although the 2,3-derivative induced mitotic chromosomal loss in the presence of an inducer of chromosomal malsegregation [6]. More recent studies have revealed the 2,3-and 3,4-isomers to be several fold more acutely toxic over 4 and 24 hr compared to the 2,5-isomer in a number of neural and astrocytic cell lines [7] and they are also capable of disrupting the cell cycle and causing apoptosis in the human SK-N-SH neuroblastoma cell line [8].To date, there have been no comparative studies aimed at determining if the 2,3-and 3,4-hexanediones illustrate any degree of specific toxicity towards neuroblastoma lines or are cytotoxic to human cell lines in general. Hence, the cytotoxicity of the three hexanedione derivatives was evalua...

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Section: Discussionsupporting

confidence: 55%

A Comparison of the Apoptotic and Cytotoxic Effects of Hexanedione Derivatives on Human Non‐Neuronal Lines and the Neuroblastoma Line SH‐SY5Y

Coleman

Zilz

Griffiths

et al. 2007

Basic Clin Pharma Tox

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“…Specifically, overexpression of Gα s in the SH-SY5Y neuroblastoma cell line augmented apoptosis induced by serum starvation, hydrogen peroxide and tunicamycin. However, in this same SH-SY5Y neuroblastoma cell line, the transgenic expression of a constitutively activated Gα s inhibited hydrogen peroxide induced apoptosis by preventing the transcriptional upregulation of BAK and downregulation of Bcl-xL [46]. Similar effects were seen upon treatment of non-transfected SH-SY5Y cells with prostaglandin E2, a Gα s agonist, and these effects were mediated by cAMP production and PKA activation.…”

Section: Review Of Literature On G Protein Regulation Of Apoptosismentioning

confidence: 98%

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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“…G␣ protein overexpression in neuronal cells increased sensitivity to apoptotic stimuli that was independent of cAMP and PKA activity (9). In renal tubular epithelium, tumor necrosis factor ␣-induced apoptosis that was associated with activation of NF-B through a pertussis toxin-sensitive G protein pathway (4).…”

Section: Discussionmentioning

confidence: 99%

Gα12 Stimulates Apoptosis in Epithelial Cells through JNK1-mediated Bcl-2 Degradation and Up-regulation of IκBα

Yanamadala

Negoro

Gunaratnam

et al. 2007

Journal of Biological Chemistry

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Apoptosis is an essential mechanism for the maintenance of somatic tissues, and when dysregulated can lead to numerous pathological conditions. G proteins regulate apoptosis in addition to other cellular functions, but the roles of specific G proteins in apoptosis signaling are not well characterized. G␣ 12 stimulates protein phosphatase 2A (PP2A), a serine/threonine phosphatase that modulates essential signaling pathways, including apoptosis. Herein, we examined whether G␣ 12 regulates apoptosis in epithelial cells. Inducible expression of G␣ 12 or constitutively active (QL)␣ 12 in Madin-Darby canine kidney cells led to increased apoptosis with expression of QL␣ 12 , but not G␣ 12 . Inducing QL␣ 12 led to degradation of the anti-apoptotic protein Bcl-2 (via the proteasome pathway), increased JNK activity, and up-regulated I B␣ protein levels, a potent stimulator of apoptosis. Furthermore, the QL␣ 12 -stimulated activation of JNK was blocked by inhibiting PP2A. To characterize endogenous G␣ 12 signaling pathways, non-transfected MDCK-II and HEK293 cells were stimulated with thrombin. Thrombin activated endogenous G␣ 12 (confirmed by GST-tetratricopeptide repeat (TPR) pull-downs) and stimulated apoptosis in both cell types. The mechanisms of thrombin-stimulated apoptosis through endogenous G␣ 12 were nearly identical to the mechanisms identified in QL␣ 12 -MDCK cells and included loss of Bcl-2, JNK activation, and up-regulation of I B␣. Knockdown of the PP2A catalytic subunit in HEK293 cells inhibited thrombin-stimulated apoptosis, prevented JNK activation, and blocked Bcl-2 degradation. In summary, G␣ 12 has a major role in regulating epithelial cell apoptosis through PP2A and JNK activation leading to loss of Bcl-2 protein expression. Targeting these pathways in vivo may lead to new therapeutic strategies for a variety of disease processes.

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Gαs sensitizes human SH-SY5Y cells to apoptosis independently of the protein kinase A pathway

Cited by 6 publications

References 52 publications

A Comparison of the Apoptotic and Cytotoxic Effects of Hexanedione Derivatives on Human Non‐Neuronal Lines and the Neuroblastoma Line SH‐SY5Y

A Comparison of the Apoptotic and Cytotoxic Effects of Hexanedione Derivatives on Human Non‐Neuronal Lines and the Neuroblastoma Line SH‐SY5Y

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

Gα12 Stimulates Apoptosis in Epithelial Cells through JNK1-mediated Bcl-2 Degradation and Up-regulation of IκBα

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