Serum withdrawal kills U937 cells by inducing a positive mutual interaction between reactive oxygen species and phosphoinositide 3-kinase

Lee, Seung Bum; Cho, Eun Sook; Yang, Hyun Sook; Kim, Hoguen; Um, Hong‐Duck

doi:10.1016/j.cellsig.2004.07.001

Cited by 31 publications

(38 citation statements)

References 41 publications

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“…Exposure of cervical cancer cells with ionizing radiation induced PI3K activity, and inhibition of PI3K effectively attenuated radiation-induced cell death, suggesting that PI3K is responsible for the enhancement of radiation sensitivity in cervical cancer cells. Our findings coincide with recent reports that PI3K is positively implicated in apoptotic response to various stimuli, including hypoxia (23), arsenic compounds (24), glucose deprivation (25), and serum withdrawal (26). Moreover, we provide further evidence that PI3K is associated with activation of the SEK-1/MKK-4-JNK pathway in response to radiation.…”

Section: Discussionsupporting

confidence: 80%

“…For example, PI3K is positively implicated in apoptosis induction in response to various stimuli, including hypoxia (23), arsenic compounds (24), glucose deprivation (25), and serum withdrawal (26). These findings indicate that PI3K activates two functionally opposite pathways, depending on cell type, nature of stimulus, and activities of other signaling pathways.…”

Section: Introductionmentioning

confidence: 89%

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Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Kim

Choi

Park

et al. 2008

Molecular Cancer Research

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Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 89%

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Kim

Choi

Park

et al. 2008

Molecular Cancer Research

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“…The activation of PI3-K/Akt has been shown to be required for the induction of apoptosis by selected apoptotic stimuli like CD95, cisplatin, arsenite, TNF, serum withdrawal, hypoxia in some defined experimental systems (Aki et al, 2001(Aki et al, , 2003Lee et al, 2005;Lu et al, 2006;Nimbalkar et al, 2003;Ono et al, 2004;Shack et al, 2003).…”

Section: Pro-cell Death Function Of Pi3-k/akt Pathwaymentioning

confidence: 99%

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

Maddika¹,

Ande²,

Panigrahi³

et al. 2007

Drug Resistance Updates

408

302

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The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16 Ink4a , p15 Ink4b , p18 Ink4c , p19 Ink4d ), and the Cip1/Waf1/Kip1-2-family (p21 Cip1/Waf1 , p27 Kip1 , p57 Kip2 ) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X L Mcl-1 L ; Bax, Bok/Mtd, Bak, and Bcl-X S ; Bad, Bid, Bim EL , Bmf, Mcl-1 S ) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G 1 -S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

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“…PI3K activity in the immune complexes was analyzed by an in vitro kinase assay using L-α-phosphatidylinositol (SigmaAldrich) as a substrate and by TLC (32).…”

Section: Pi3k Assaymentioning

confidence: 99%

Phospholipase A2 Activity of Peroxiredoxin 6 Promotes Invasion and Metastasis of Lung Cancer Cells

Lee

et al. 2010

Molecular Cancer Therapeutics

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Peroxiredoxins (PRDX) are a family of thiol-dependent peroxidases. Among the six mammalian members of this family, PRDX6 is the only protein that additionally exhibits phospholipase A 2 (PLA 2 ) activity. The physiologic role of this interesting PRDX6 feature is largely unknown at present. In this study, we show that PRDX6 increases the metastatic potential of lung cancer cells. Functional analyses of the enzymatic activities of PRDX6, using specific pharmacologic inhibitors and mutagenesis studies, reveal that both peroxidase and PLA 2 activities are required for metastasis. Specifically, peroxidase activity facilitates the growth of cancer cells, and PLA 2 activity promotes invasiveness. Further investigation of the latter event discloses that PLA 2 activity promotes accumulation of arachidonic acid, which, in turn, induces the invasive pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and urokinase-type plasminogen activator. This study is the first to define the functions of the enzymatic activities of PRDX6 in metastasis and to show the involvement of arachidonic acid in PRDX6 action in intact cells. These novel findings provide a significant step toward elucidating the role of PRDX6 in cancer and the mechanism of its action.

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Serum withdrawal kills U937 cells by inducing a positive mutual interaction between reactive oxygen species and phosphoinositide 3-kinase

Cited by 31 publications

References 41 publications

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

Phospholipase A2 Activity of Peroxiredoxin 6 Promotes Invasion and Metastasis of Lung Cancer Cells

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