PKC 412 sensitizes U1810 non-small cell lung cancer cells to DNA damage

Hemström, Therese H; Joseph, Bertrand; Schulte, Gunnar; Lewensohn, Rolf; Zhivotovsky, Boris

doi:10.1016/j.yexcr.2004.12.017

Cited by 18 publications

(20 citation statements)

References 43 publications

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“…Earlier, 14 we showed that PKC 412 and Ro 31-8220 had opposite effects on AKT phosphorylation: PKC 412 decreased while Ro 31-8220 increased the phosphorylation level in a concentration-dependent manner. Both agents were also shown to decrease the phosphorylation of ERK, PKC 412 being the most potent inhibitor.…”

Section: Resultsmentioning

confidence: 70%

“…Earlier 14 we showed that the order of exposure of cells to chemotherapy agents increased the treatment efficiency. Post-treatment of VP-16-or radiation-exposed cells with PKC 412 being inferior to co-/or pre-treatment of cells.…”

Section: Incubation Of Vp-16-treated Nsclc Cells With Ly-294002 Wortmentioning

confidence: 97%

“…14 PKC 412 also sensitizes U1810 cells to treatment with etoposide and radiation. Interestingly, single treatment of cells with PKC 412 leads to the formation of tetraploid cells, indicating that PKC 412 disturbs mitosis-related signaling.…”

mentioning

confidence: 99%

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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: Resultsmentioning

confidence: 70%

Section: Incubation Of Vp-16-treated Nsclc Cells With Ly-294002 Wortmentioning

confidence: 97%

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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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“…[11][12][13] However, the mechanisms by which AIF release is regulated have not yet been established conclusively. Therefore, in this study, we focused on the molecular mechanisms of AIF processing and release.…”

Section: Discussionmentioning

confidence: 99%

“…We have reported earlier that malfunction of AIF release from mitochondria is essential for the chemoresistance of U1810 NSCLC cells, as the activation of caspases alone was not sufficient to kill these cells. [11][12][13] However, we also found that staurosporine (STS) can reactivate the full apoptotic machinery in U1810 cells. This suggests an important function for the AIF-mediated cell death pathway in NSCLCs.…”

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confidence: 91%

An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release AIF during cell death

et al. 2008

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Apoptosis-inducing factor (AIF), a flavoprotein with NADH oxidase activity anchored to the mitochondrial inner membrane, is known to be involved in complex I maintenance. During apoptosis, AIF can be released from mitochondria and translocate to the nucleus, where it participates in chromatin condensation and large-scale DNA fragmentation. The mechanism of AIF release is not fully understood. Here, we show that a prolonged (B10 min) increase in intracellular Ca 2 þ level is a prerequisite step for AIF processing and release during cell death. In contrast, a transient ATP-induced Ca 2 þ increase, followed by rapid normalization of the Ca 2 þ level, was not sufficient to trigger the proteolysis of AIF. Hence, import of extracellular Ca 2 þ into staurosporine-treated cells caused the activation of a calpain, located in the intermembrane space of mitochondria. The activated calpain, in turn, cleaved membrane-bound AIF, and the soluble fragment was released from the mitochondria upon outer membrane permeabilization through Bax/Bak-mediated pores or by the induction of Ca 2 þ -dependent mitochondrial permeability transition. Inhibition of calpain, or chelation of Ca 2 þ , but not the suppression of caspase activity, prevented processing and release of AIF. Combined, these results provide novel insights into the mechanism of AIF release during cell death.

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Combination of Antiangiogenic Therapy with Other Anticancer Therapies

Teicher¹

2008

Angiogenesis

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PKC 412 sensitizes U1810 non-small cell lung cancer cells to DNA damage

Cited by 18 publications

References 43 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

An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release AIF during cell death

Combination of Antiangiogenic Therapy with Other Anticancer Therapies

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