Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy

Fulda, Simone; Debatin, Klaus‐Michael

doi:10.1038/sj.onc.1209608

Cited by 2,009 publications

(1,629 citation statements)

References 163 publications

(207 reference statements)

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“…Caspase activation and death signaling was suppressed by the universal inhibitor of caspases, zVAD-fmk. Enhancing effects of CHX on TRAILinduced death signaling were probably due to translational suppression of short-lived protein inhibitors of apoptosis, including cFLIP [33,34].…”

Section: Cell Death In Human Melanomas Induced By Either Recombinant mentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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Section: Cell Death In Human Melanomas Induced By Either Recombinant mentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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“…5,6 Apoptosis occurs through two main signaling pathways: an extrinsic pathway that utilizes a diversified group of cell surface death receptors; [7][8][9][10][11][12][13][14] and an intrinsic pathway that utilizes various intracellular organelles to execute the programmed cell death machinery. [15][16][17][18][19][20] An important and well-studied point of control for both the extrinsic and intrinsic apoptotic pathways is the Bcl-2 family of proteins that comprise both pro-and antiapoptotic members and regulate the apoptotic program through a tightly controlled series of checks and balances. 21,22 Resistance to cell death is a common feature in many disease states that impedes both therapy and treatment.…”

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confidence: 99%

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

et al. 2015

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We developed a model system to investigate apoptotic resistance in T cells using osmotic stress (OS) to drive selection of deathresistant cells. Exposure of S49 (Neo) T cells to multiple rounds of OS followed by recovery of surviving cells resulted in the selection of a population of T cells (S49 ) that failed to die in response to a variety of intrinsic apoptotic stimuli including acute OS, but remained sensitive to extrinsic apoptotic initiators. Genome-wide microarray analysis comparing the S49 (OS 4-25) with the parent S49 (Neo) cells revealed over 8500 differentially regulated genes, with almost 90% of those identified being repressed. Surprisingly, our data revealed that apoptotic resistance is not associated with expected changes in pro-or antiapoptotic Bcl-2 family member genes. Rather, these cells lack several characteristics associated with the initial signaling or activation of the intrinsic apoptosis pathway, including failure to increase mitochondrial-derived reactive oxygen species, failure to increase intracellular calcium, failure to deplete glutathione, failure to release cytochrome c from the mitochondria, along with a lack of induced caspase activity. The S49 (OS 4-25) cells exhibit metabolic characteristics indicative of the Warburg effect, and, despite numerous changes in mitochondria gene expression, the mitochondria have a normal metabolic capacity. Interestingly, the S49 (OS 4-25) cells have developed a complete dependence on glucose for survival, and glucose withdrawal results in cell death with many of the essential characteristics of apoptosis. Furthermore, we show that other dietary sugars such as galactose support the viability of the S49 (OS 4-25) cells in the absence of glucose; however, this carbon source sensitizes these cells to die. Our findings suggest that carbon substrate reprogramming for energy production in the S49 (OS 4-25) cells results in stimulusspecific recognition defects in the activation of intrinsic apoptotic pathways.

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“…Oncogene ( Keywords: apoptosis; PI3K; neuroblastoma; chemotherapy Intact apoptosis pathways are critical for chemotherapyinduced cytotoxicity and are initiated through the death receptor (extrinsic) pathway or the mitochondrial (intrinsic) pathway, resulting in activation of caspases (Fulda and Debatin, 2006). Mitochondrial outer membrane permeabilization is tightly controlled by the Bcl-2 family of proteins, for example, antiapoptotic members such as Bcl-2, Bcl-X L and Mcl-1 and pro-apoptotic molecules such as Bax, Bak and BH3 domain only molecules (Adams and Cory, 2007).…”

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confidence: 99%

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

et al. 2010

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We recently identified activation of phosphatidylinositol 3 0 -kinase (PI3K)/Akt as a novel predictor of poor outcome in neuroblastoma. Here, we investigated the effect of smallmolecule PI3K inhibitors on chemosensitivity. We provide first evidence that PI3K inhibitors, for example PI103, synergize with various chemotherapeutics (Doxorubicin, Etoposide, Topotecan, Cisplatin, Vincristine and Taxol) to trigger apoptosis in neuroblastoma cells (combination index: high synergy). Mechanistic studies reveal that PI103 cooperates with Doxorubicin to reduce Mcl-1 expression and Bim EL phosphorylation and to upregulate Noxa and Bim EL levels. This shifted ratio of pro-and antiapoptotic Bcl-2 proteins results in increased Bax/Bak conformational change, loss of mitochondrial membrane potential, cytochrome c release, caspase activation and caspase-dependent apoptosis. Although Mcl-1 knockdown enhances Doxorubicin-and PI103-induced apoptosis, silencing of Noxa, Bax/ Bak or p53 reduces apoptosis, underscoring the functional relevance of the Doxorubicin-and PI103-mediated modulation of these proteins for chemosensitization. Bcl-2 overexpression inhibits Bax activation, mitochondrial perturbations, cleavage of caspases and Bid, and apoptosis, confirming the central role of the mitochondrial pathway for chemosensitization. Interestingly, the broad-range caspase inhibitor zVAD.fmk does not interfere with Bax activation or mitochondrial outer membrane permeabilization, whereas it blocks caspase activation and apoptosis, thus placing mitochondrial events upstream of caspase activation. Importantly, PI103 and Doxorubicin cooperate to induce apoptosis and to suppress tumor growth in patients' derived primary neuroblastoma cells and in an in vivo neuroblastoma model, underlining the clinical relevance of the results. Thus, targeting PI3K presents a novel and promising strategy to sensitize neuroblastoma cells for chemotherapy-induced apoptosis, which has important implications for the development of targeted therapies for neuroblastoma.

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Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy

Cited by 2,009 publications

References 163 publications

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

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