Peroxiredoxin 6 interferes with TRAIL-induced death-inducing signaling complex formation by binding to death effector domain caspase

Choi, Hyung-Seok; Chang, Jae Won; Jung, Yong‐Keun

doi:10.1038/cdd.2010.113

Cited by 36 publications

(30 citation statements)

References 39 publications

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“…Various mechanisms of resistance have been proposed some of which include regulation of pro-apoptotic receptor transport to the cell membrane, 18 Bcl-2-mediated downregulation of a mitochondrial machinery, 19 bax mutations, 20 XIAP inhibition 21 and peroxiredoxin 6 interference, 22 or downregulation of Mcl-1 or STAT3 when sorfenib is used in combination with TRAIL. 23,24 Previously, we have demonstrated that c-Fos-mediated inhibition of c-FLIP(L) is an important pathway in regulating resistance to TRAIL.…”

Section: Discussionmentioning

confidence: 99%

F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway

Wang

Zeng

et al. 2011

Cell Death Differ

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptotic death of human cancer cells while sparing normal human cells. Although TRAIL holds great promise as a potential anticancer agent, some tumors develop resistance to TRAIL. Previously, we have shown that the activator protein 1 (AP-1) family member, c-Fos, is an important modulator of apoptosis. Although F-box protein 10 (FBXL10) has been implicated to regulate an AP-1 family protein, c-Jun, its role in mediating apoptotic pathways has not been previously investigated. Here, we report that FBXL10 is a transcriptional repressor of c-Fos and a target gene of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB)-p65 in human cancers. We demonstrate that FBXL10 is an important anti-apoptotic molecule, which directly binds and represses c-Fos promoter in order for cancer cells to resist TRAIL-induced apoptosis. FBXL10 indirectly regulates c-FLIP(L) levels via c-Fosdependent pathways. Silencing of FBXL10 sensitizes resistant cells to TRAIL, while, overexpression of FBXL10 represses TRAILinduced apoptosis. Moreover, our results indicate that expression of FBXL10 functions via an NF-jB-dependent pathway, and TRAIL or proteasome inhibitors downregulate FBXL10 via inhibiting NF-jB signaling. Taken together, we find a novel functional role for FBXL10 as an anti-apoptotic molecule, and describe a new apoptotic-related pathway that involves NF-jB/FBXL10/c-Fos/ c-FLIP. Therefore, silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies.

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Section: Discussionmentioning

confidence: 99%

F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway

Wang

Zeng

et al. 2011

Cell Death Differ

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“…Recent findings suggest a protumorigenic function of Prdx6 due to its effect on tumor cell proliferation, apoptosis, and invasiveness. Prdx6 interfered with TRAIL-or cisplatin-induced apoptosis in human cancer cells in vitro (15,16). Furthermore, it enhanced the metastatic potential of breast and lung cancer cells in orthotopic cancer models (17,18).…”

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confidence: 99%

Dual Role of the Antioxidant Enzyme Peroxiredoxin 6 in Skin Carcinogenesis

et al. 2013

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The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8-induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis. Cancer Res; 73(11); 3460-9. Ó2013 AACR.

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“…13 Furthermore, a recent report has shown that Prdx6 modulates TRAIL signaling. 17 These results suggest that PLA 2 activity of Prdx6 is related to TNFR-mediated apoptosis. To test the possibility, wt BEAS-2B and Prdx6…”

Section: Resultsmentioning

confidence: 61%

“…9,10 The cellular functions of iPLA 2 are known to be responsible for phospholipid remodeling as a housekeeping function and for generation of arachidonic acid (AA) and lysophospholipid, which are closely related to multicellular functions, such as cell proliferation, apoptosis, and inflammatory events. [11][12][13][14][15][16] Although a recent report showed that Prdx6 interferes with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced death-inducing signaling complex formation by binding to the death effector domain of caspase, 17 the inhibitory effect seemed to be independent of its enzymatic activity, that is, its peroxidase and iPLA 2 activity. Considering many functions of cellular iPLA 2 , the iPLA 2 activity of Prdx6 may be also implicated in controlling cell fate in response to a variety of stimuli.…”

Section: Introductionmentioning

confidence: 99%

Phospholipase A2 of peroxiredoxin 6 has a critical role in tumor necrosis factor-induced apoptosis

Chun

2011

Cell Death Differ

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Peroxiredoxin 6 (Prdx6) is a bifunctional enzyme with peroxidase and phospholipase A 2 (PLA 2 ) activities. Although the cellular function of the peroxidase of Prdx6 has been well elucidated, the function of the PLA 2 of Prdx6 is largely unknown. Here, we report a novel function for the PLA 2 in regulating TNF-induced apoptosis through arachidonic acid (AA) release and interleukin-1b (IL-1b) production. Prdx6 knockdown (Prdx6 KD ) in human bronchial epithelial cells (BEAS2B) shows severe decreases of peroxidase and PLA 2 activities. Surprisingly, Prdx6KD cells are markedly resistant to apoptosis induced by TNF-a in the presence of cycloheximide, but are highly sensitive to hydrogen peroxide-induced apoptosis. Furthermore, the release of AA and the production of IL-1b induced by proinflammatory stimuli, such as TNF-a, LPS, and poly I/C, are severely decreased in Prdx6 KD cells. More interestingly, the restoration of Prdx6 expression with wild-type Prdx6, but not PLA 2 -mutant Prdx6 (S32A), in Prdx6 KD cells dramatically induces the recovery of TNF-induced apoptosis, AA release, and IL-1b production, indicating specific roles for the PLA 2 activity of Prdx6. Our results provide new insights into the distinct roles of bifunctional Prdx6 with peroxidase and PLA 2 activities in oxidative stress-induced and TNF-induced apoptosis, respectively.

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Peroxiredoxin 6 interferes with TRAIL-induced death-inducing signaling complex formation by binding to death effector domain caspase

Cited by 36 publications

References 39 publications

F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway

F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway

Dual Role of the Antioxidant Enzyme Peroxiredoxin 6 in Skin Carcinogenesis

Phospholipase A2 of peroxiredoxin 6 has a critical role in tumor necrosis factor-induced apoptosis

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