Phosphoinositide 3-kinase and Forkhead, a switch for cell division

Martínez-Gac, Lorena; Álvarez, Beatriz; García, Zaira; Marqués, Miriam; Arrizabalaga, M.; Carrera, Ana C.

doi:10.1042/bst0320360

Cited by 35 publications

(31 citation statements)

References 16 publications

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“…8 It is known that PI3-kinase activity is able to increase the level of cyclin E and D and to inhibit FOXO transcription factors that regulate transcription of proteins essential for the G1/S transition, such as p27. 31 This observation might explain the accumulation of G1 cells upon treatment with wortmannin and LY-294002.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Hemström

Sandström

Zhivotovsky

2006

Intl Journal of Cancer

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Non-small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemstr€ om et al., Exp Cell Res 2005;305:200-13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3-kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3-kinase inhibitors LY-294002 and wortmannin, the Akt activator Ro 31-8220, the MEK inhibitor PD 98059 and PKC 412. PI3-kinase inhibitors induced apoptosis-like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA-damaging drug VP-16, while Ro 31-8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3-kinase inhibition and VP-16. Key words: mitotic catastrophe; non-small cell lung carcinoma; PI3-kinase; Akt; apoptosis Cell lines derived from non-small cell lung carcinoma (NSCLC) are most often characterized by cellular resistance towards anticancer drugs and radiation. 1 Efficiency of action of DNA-damaging drugs used in anticancer therapy depends on the successful ability to induce growth arrest and to activate the cell death machinery. 2 Apoptosis induced by DNA damage is typically associated with activation of a family of proteases, the caspases, as a result of a sequence of mitochondria-mediated events. The caspases cleave many proteins, eventually leading to biochemical and morphological apoptosis-specific changes. In addition to activation of the caspases, mediated by release of cytochrome c, several proteins, such as apoptosis inducing factor (AIF) and endonuclease G are also released from mitochondria, translocate to the nuclei and induce chromatin condensation and cell death independently of caspases.Cell cycle regulation is also an important determinant for efficiency of cell death in response to DNA damage. For example, topoisomerase inhibitors are suggested to be particularly effective in S-phase when DNA replication occurs, 3 while irradiated cells are most sensitive at G2/M phase. 4 DNA-damaged cells are removed by cell death following activation of the DNA damage checkpoints in G1 and G2-phases of the cell cycle. 5 There are many mechanisms for cells being resistant to DNA damage. 6 For example, resistant lung cancer cells have an increased activity of DNAdependent protein kinase (DNA-PK) and DNA repair, correlating with a decreased incidence of cell death, suggesting involvement of DNA-PK in tumor survival. 7,8 Aberrant signaling of other kinases, such as the Ras/MEK/ERK and PI3-kinase/Akt pathways is also contributes to cell death resistance. In NSCLC-patients phospho-Akt overexpression confers a stage-independent survival disadvantage 9 and in NSCLC cell lines a high activity of Akt promotes cellular...

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Section: Discussionmentioning

confidence: 99%

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Hemström

Sandström

Zhivotovsky

2006

Intl Journal of Cancer

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“…This is of importance, because Akt phosphorylation of FKHR Ser 256 is critical to the ability of growth factors to suppress FKHR-dependent transcription, thereby preventing FKHR from inducing cell cycle arrest and apoptosis through transcriptional regulation of p27 (kip1; ref. 27) and FKHR-controlled Fas ligand expression (28 -30 pentamer for 48 and 72 h and corresponding DMSO-treated controls were analyzed by immunoblotting analysis. A total of six membranes were generated from the same gel and each membrane was probed with different specific antibody-recognizing endogenous p53 and four different phosphorylation residues of p53 that were suspected to be affected by pentamer after initial screening using multilayered dot blot.…”

Section: Discussionmentioning

confidence: 99%

Pentameric procyanidin from Theobroma cacao selectively inhibits growth of human breast cancer cells

Ramljak

Romanczyk²,

Metheny-Barlow

et al. 2005

Molecular Cancer Therapeutics

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A naturally occurring, cocoa-derived pentameric procyanidin (pentamer) was previously shown to cause G 0 /G 1 cell cycle arrest in human breast cancer cells by an unknown molecular mechanism. Here, we show that pentamer selectively inhibits the proliferation of human breast cancer cells (MDA MB-231, MDA MB-436, MDA MB-468, SKBR-3, and MCF-7) and benzo(a)pyreneimmortalized 184A1N4 and 184B5 cells. In contrast, normal human mammary epithelial cells in primary culture and spontaneously immortalized MCF-10A cells were significantly resistant. We evaluated whether this differential response to pentamer may involve depolarization of the mitochondrial membrane. Pentamer caused significant depolarization of mitochondrial membrane in MDA MB231 cells but not the more normal MCF-10A cells, whereas other normal and tumor cell lines tested gave variable results. Further investigations, using a proteomics approach with pentamer-treated MDA MB-231, revealed a specific dephosphorylation, without changes in protein expression, of several G 1 -modulatory proteins: Cdc2 (at Tyr 15 ), forkhead transcription factor (at Ser 256 , the Akt phosphorylation site) and p53 (Ser 392 ). Dephosphorylation of p53 (at Ser 392 ) by pentamer was confirmed in MDA MB-468 cells. However, both expression and phosphorylation of retinoblastoma protein were decreased after pentamer treatment. Our results show that breast cancer cells are selectively susceptible to the cytotoxic effects of pentameric procyanidin, and suggest that inhibition of cellular proliferation by this compound is associated with the site-specific dephosphorylation or down-regulation of several cell cycle regulatory proteins. [Mol Cancer Ther 2005;4(4): 537 -46]

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“…Cyclin D1 and cyclin E are two of the major cyclins involved in cell cycle progression and p21, p27, and p57 are three CKI, which bind to the cyclin-Cdk2 complex to inhibit the kinase activity and prevent transition to the S phase (10,37). Cyclins and CKI are regulated by transcriptional and posttranscriptional-dependent mechanisms that are linked to a variety of signaling pathways including PI3K/Akt and ERK1/2 (9,22,23,31). Recently, it was reported that Src and Fyn can directly phosphorylate p27 at tyrosine residues, and promote its degradation by the SCF-SKP2 ubiquitin-proteasome pathway in breast cancer cells (4,11).…”

mentioning

confidence: 99%

Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms

Xing¹,

Zhu²,

Mao³

et al. 2008

American Journal of Physiology-Renal Physiology

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Xing J, Zhang Z, Mao H, Schnellmann RG, Zhuang S. Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms. Am J Physiol Renal Physiol 295: F145-F152, 2008. First published April 23, 2008 doi:10.1152/ajprenal.00092.2008.-Our recent studies showed that Src family kinases (SFKs) are important mediators of proliferation in renal proximal tubular cells (RPTC). In this study, we elucidate the signaling mechanisms that mediate SFK regulation of cell proliferation and cycle protein expression, and identify the SFK member responsible for these responses in a mouse RPTC line. Akt, a target of phosphoinositide-3-kinase (PI3K), and ERK1/2 were constitutively phosphorylated in RPTC cultured in the presence of serum. While treatment of cells with PP1, a specific SFK inhibitor, completely blocked phosphorylation of ERK1/2 and Akt, only inhibition of PI3K/Akt resulted in decreased RPTC proliferation. Incubation of cells with PP1 decreased cyclin D1 expression, decreased p27 and p57 phosphorylation, and increased p27 and p57 expression, two cyclin-dependent kinase inhibitors. Inhibition of the PI3K pathway decreased expression of cyclin D1 without altering expression of p27 and p57. In contrast, PP1 and PI3K inhibition had no effect on cyclin E and p21. Although RPTC expressed Src, Fyn, and Lyn, only siRNA-mediated knockdown of Src decreased RPTC proliferation, decreased cyclin D1 expression, and increased p27 and p57 expression. These data reveal that Src is a crucial mediator of RPTC proliferation and Src-mediated proliferation is associated with PI3K-dependent upregulation of cyclin D1 and PI3K-independent downregulation of p27 and p57.

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Phosphoinositide 3-kinase and Forkhead, a switch for cell division

Cited by 35 publications

References 16 publications

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Pentameric procyanidin from Theobroma cacao selectively inhibits growth of human breast cancer cells

Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms

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