Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells

Song, Xinxin; Kim, S. Y.; Zhou, Zhigang; Lagasse, Eric; Kwon, Yong Tae; Lee, Y. J.

doi:10.1038/cddis.2013.104

Cited by 26 publications

(25 citation statements)

References 46 publications

(54 reference statements)

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“…We observed that no restoration of c-FLIPL occurred during treatment with SP6001125. This observation was consistent with other researchers’ reports [27,28]. …”

Section: Resultssupporting

confidence: 94%

“…We observed in Figure 5C that 25% of protein synthesis was inhibited in hyperthermia, whereas there was 46% protein synthesis inhibition in oxaliplatin combined with hyperthermia. Figure 5D shows that reduction of c-FLIP L level by 42°C for 1 h heating alone was more than that by 30 µg of cyclohexmide which inhibits protein synthesis by 99% [28]. These results suggest that protein synthesis inhibition alone is not a major factor for downregulation of FLIP L by hyperthermia.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

Song

Kim

2013

PLoS ONE

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Colorectal cancer is the third leading cause of cancer-related mortality in the world-- the main cause of death from colorectal cancer is hepatic metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of oxaliplatin concomitantly with hyperthermia and humanized death receptor 4 (DR4) antibody mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human colon cancer cell lines CX-1 and HCT116 as well as human colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular FLICE inhibitory protein long isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at lysine residue (K) 195 and protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic metastases who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway.

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“…We observed that no restoration of c-FLIPL occurred during treatment with SP6001125. This observation was consistent with other researchers’ reports [27,28]. …”

Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

Song

Kim

2013

PLoS ONE

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“…Previous studies presented that many proteins including survivin and c-FLIP are degraded through activation of ubiquitination [45][46][47]. To confirm the effect of ubiquitination on degradation of survivin and c-FLIP expression, we analyzed ubiquitination of survivin and c-FLIP by honokiol.…”

Section: Honokiol Induces Survivin and C-flip Degradation Through Actmentioning

confidence: 99%

Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation

et al. 2019

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Honokiol is a natural biphenolic compound extracted from traditional Chinese medicine Magnolia species, which have been known to display various biological effects including anti-cancer, anti-proliferative, anti-angiogenic, and anti-metastatic activities in cancer cells. Here, we found that honokiol sensitizes cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through downregulation of anti-apoptotic proteins survivin and c-FLIP. Ectopic expression of survivin and c-FLIP markedly abolished honokiol and TRAIL-induced apoptosis. Mechanistically, honokiol induced protein degradation of c-FLIP and survivin through STAMBPL1, a deubiquitinase. STAMBPL1 interacted with survivin and c-FLIP, resulted in reduction of ubiquitination. Knockdown of STAMBPL1 reduced survivin and c-FLIP protein levels, while overexpression of STAMBPL1 inhibited honokinol-induced survivin and c-FLIP degradation. Our findings provided that honokiol could overcome TRAIL resistance through survivin and c-FLIP degradation induced by inhibition of STAMBPL1 expression.

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“…Although the preclinical/clinical studies demonstrated the safety and activity of TRAIL, its short elimination half-life (approximately 30 min) is a main obstacle (3, 4). To overcome this obstacle, researchers have devised several strategies, including using humanized anti-TRAIL receptor antibodies (5–8) and a chimeric human TRAIL/human IgG-Fc fusion protein (9). In this study, we attempted to develop secretory TRAIL-natural killer (NK) cell-based therapy.…”

Section: Introductionmentioning

confidence: 99%

Secretory TRAIL-Armed Natural Killer Cell–Based Therapy: In Vitro and In Vivo Colorectal Peritoneal Carcinomatosis Xenograft

Song

Hong

Kwon

et al. 2016

Molecular Cancer Therapeutics

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Since its discovery in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest among oncologists due to its remarkable ability to induce apoptosis in malignant human cells, but not in most normal cells. However, one major drawback is its fast clearance rate in vivo. Thus, the development of an alternative means of delivery may increase the effectiveness of TRAIL-based therapy. In this study, we developed a secretory TRAIL-armed natural killer (NK) cell-based therapy and assessed its cytotoxic effects on colorectal cancer cells and its tumoricidal efficacy on colorectal peritoneal carcinomatosis xenograft. We generated genetically modified NK cells by transduction with a lentiviral vector consisting of a secretion signal domain, a trimerization domain, and an extracellular domain of the TRAIL gene. These NK cells secreted a glycosylated form of TRAIL fusion protein that induced apoptotic death. Intraperitoneally, but not intravenously, injected NK cells effectively accumulated at tumor sites, infiltrated tumor tissue, induced apoptosis, and delayed tumor growth. These results shed light on the therapeutic potential of genetically engineered NK cells to treat peritoneal carcinomatosis. Mol Cancer Ther; 15(7); 1591-601. Ó2016 AACR.

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Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells

Cited by 26 publications

References 46 publications

Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation

Secretory TRAIL-Armed Natural Killer Cell–Based Therapy: In Vitro and In Vivo Colorectal Peritoneal Carcinomatosis Xenograft

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