Rottlerin synergistically enhances imatinib-induced apoptosis of BCR/ABL-expressing cells through its mitochondrial uncoupling effect independent of protein kinase C-δ

Kurosu, Tetsuya; Tsuji, Kohei; Kida, Akiko; Koyama, Takatoshi; Yamamoto, Masahide; Miura, Osamu

doi:10.1038/sj.onc.1210117

Cited by 30 publications

(40 citation statements)

References 40 publications

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“…The above results clearly show the prevention of TNF-induced necrosis by rottlerin in L929 cells, even though several reports have demonstrated that rottlerin induces apoptosis (Tillman et al, 2003;Kurosu et al, 2007). This suggests that rottlerin may have an opposing regulatory role between apoptotic and necrotic modes of cell death upon death-receptor ligation.…”

Section: Rottlerin Sensitizes Murine Fibrosarcoma L929 Cells Against mentioning

confidence: 63%

“…Results of recent studies have demonstrated that rottlerin sensitizes some cancer cells to deathreceptor-or chemotherapeutic-agent-induced apoptosis in a manner independent of PKCδ activity (Tillman et al, 2003;Kurosu et al, 2007). To examine the possible involvement of PKCδ in the prevention of TNF-induced necrosis by rottlerin, we introduced adenovirus expressing wild-type (WT) and dominant-negative (DN) forms of PKCδ into L929 cells were pretreated with GA (1 μM) for 12 h, followed by treatment with TNF (15 ng/ml) for 5 h. Cells were immediately photographed under electron microscopy.…”

Section: Rottlerin Protects Murine Fibrosarcoma L929 Cells Against Tnmentioning

confidence: 99%

“…In one of these studies, rottlerin was reported to inhibit mitochondrial metabolism, which correlated with depletion of cellular ATP concentration and general inhibition of cellular processes (Soltoff, 2001). Of note, these recent observations have implicated the apoptosis-inducing effect of rottlerin on tumor cells, and synergistic sensitization of the cytotoxic effects of chemotherapeutic and apoptotic ligands (Tillman et al, 2003;Kurosu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase

et al. 2008

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Previous studies have demonstrated that rottlerin, a specific PKCδ inhibitor, potentiates death receptormediated apoptosis through a cytochrome c-dependent or -independent pathway. However, its ability to regulate necrotic cell death, as well as the underlying mechanism, remains unknown. We found that in murine fibrosarcoma L929 cells, treatment with rottlerin protected the cells against TNF-induced necrosis, whereas it sensitized the cells to apoptosis induced by co-treatment with Hsp90 inhibitor geldanamycin and TNF, in a manner independent of its ability to inhibit PKC-δ. TNF treatment induced rapid accumulation of mitochondrial superoxide (O2 -) through the Nox1 NADPH oxidase when cells undergo necrosis. Moreover, pretreatment with rottlerin failed to induce the GTP-bound form of small GTPase Rac1 by TNF treatment, and subsequently suppressed mitochondrial O 2 -production and poly(ADP-ribose) polymerase activation, thus inhibiting necrotic cell death. Therefore, our study suggests that Nox1 NADPH oxidase is a new molecular target for anti-necrotic activity of rottlerin upon death-receptor ligation.

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Section: Rottlerin Sensitizes Murine Fibrosarcoma L929 Cells Against mentioning

confidence: 63%

Section: Rottlerin Protects Murine Fibrosarcoma L929 Cells Against Tnmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase

et al. 2008

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“…In addition, rottlerin can inhibit many other kinases, including mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) and p38MAPK (30,36), in a dosedependent manner, whereas it has no significant effect on these kinases in OLETF rat retinas (data not shown). Therefore, this discrepancy may be due to differences in the doses of rottlerin used or in the physiological and pathological state of the animals.…”

Section: Discussionmentioning

confidence: 97%

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Kim

Park

et al. 2008

Diabetes

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OBJECTIVE-Protein kinase C (PKC)-␦, an upstream regulator of the Akt survival pathway, contributes to cellular dysfunction in the pathogenesis of diabetes. Herein, we examined the role of PKC-␦ in neuronal apoptosis through Akt in the retinas of diabetic rats.RESEARCH DESIGN AND METHODS-We used retinas from 24-and 35-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) diabetic and Long-Evans Tokushima Otsuka (LETO) nondiabetic rats. To assess whether PKC-␦ affects Akt signaling and cell death in OLETF rat retinas, we examined 1) PKC-␦ activity and apoptosis; 2) protein levels of phosphatidylinositol 3-kinase (PI 3-kinase) p85, heat shock protein 90 (HSP90), and protein phosphatase 2A (PP2A); 3) Akt phosphorylation; and 4) Akt binding to HSP90 or PP2A in LETO and OLETF retinas in the presence or absence of rottlerin, a highly specific PKC-␦ inhibitor, or small interfering RNAs (siRNAs) for PKC-␦ and HSP90.RESULTS-In OLETF retinas from 35-week-old rats, ganglion cell death, PKC-␦ and PP2A activity, and Akt-PP2A binding were significantly increased and Akt phosphorylation and Akt-HSP90 binding were decreased compared with retinas from 24-week-old OLETF and LETO rats. Rottlerin and PKC-␦ siRNA abrogated these effects in OLETF retinas from 35-week-old rats. HSP90 siRNA significantly increased ganglion cell death and Akt-PP2A complexes and markedly decreased HSP90-Akt binding and Akt phosphorylation in LETO retinas from 35-week-old rats compared with those from nontreated LETO rats.CONCLUSIONS-PKC-␦ activation contributes to neuro-retinal apoptosis in diabetic rats by inhibiting Akt-mediated signaling pathways. Diabetes 57:2181-2190, 2008 P rotein kinase C (PKC)-␦, a ubiquitously expressed isoform of the novel PKC subfamily, mediates an anti-apoptotic signaling cascade through the phosphatidylinositol 3-kinase (PI 3-kinase)-mediated survival pathway (1,2) and also promotes apoptosis by interfering with Akt signaling (3-5).Akt is a downstream target of PI 3-kinase that plays an integral role in cell survival. Dysregulation of Akt is frequently observed in diseases such as cancers and diabetes (6 -8). PI 3-kinase activates Akt through the phosphorylation of two key regulatory residues, Thr308 and Ser473, on Akt. Phosphorylation of both residues is necessary for full activation of Akt and subsequent regulation of many PI 3-kinase-mediated biological responses (9,10).Protein phosphatase 2A (PP2A), a major cellular serine/ threonine phosphatase, regulates the phosphorylation state of cellular proteins in various pathological conditions (11-13). Recently, it has been reported that PP2A is involved in the regulation of cell proliferation and survival through its ability to dephosphorylate Akt (11-15). Furthermore, heat shock protein 90 (HSP90) counteracts the effect of PP2A in cells through direct binding to Akt, protecting Akt from PP2A-mediated dephosphorylation and thus functioning as a positive regulator of Akt signaling (13,15,16). Of note, numerous reports have suggested that Akt-or HSP-mediated cytoprotection is r...

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“…23,24 We assessed the effect of treatment with FCCP alone and found that single treatment with FCCP did not induce cell death in either cell line (Supporting Information Fig. S3B).…”

Section: Increased Mitochondrial Calcium Level and Membrane Potentialmentioning

confidence: 99%

Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells

et al. 2013

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Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib-induced cell death in two different MM cell lines (bortezomib-resistant KMS20 cells and bortezomib-sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine-5 0 -triphosphate and mitochondrial Ca 21 concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2-methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision-making.

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Rottlerin synergistically enhances imatinib-induced apoptosis of BCR/ABL-expressing cells through its mitochondrial uncoupling effect independent of protein kinase C-δ

Cited by 30 publications

References 40 publications

Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase

Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells

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