Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation

Brockmann, Anette; Bluwstein, Andrej; Kögel, Annika; May, Sarah; Marx, Andreas; Tschan, Mario P.; Brunner, Thomas

doi:10.1038/cddis.2015.137

Cited by 9 publications

(6 citation statements)

References 40 publications

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“…Thus, various clinical drugs reported to activate ROS were used to separately treat melanoma cells with or without iron co-treatment. Among them, sulfasalazine (SSZ), 40 buthionine sulfoximine (BSO), 41 BAY 87-2243 (BAY), 42 phenylethyl isothiocyanate (PEITC), 41 etacrynic acid (EA), 43 and ezatiostat (TLK199) 43 could mildly elevate the ROS level in A375 cells, and this ROS elevation was substantially amplified by co-treatment of iron (Fig. 6a ; Supplementary information, Fig.…”

Section: Resultsmentioning

confidence: 99%

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

et al. 2018

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Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death, such as ferroptosis, apoptosis and necroptosis. However, whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here, we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells, iron enhanced ROS signaling initiated by CCCP, causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20, which facilitates cytochrome c release to cytosol to activate caspase-3, eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore, ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME, iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above, we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover, no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis, but also implicates a novel iron-based intervention strategy for melanoma therapy.

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Section: Resultsmentioning

confidence: 99%

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

et al. 2018

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“…Upon induction, PUMA facilitates mitochondrial outer membrane permeabilization and caspase activation cascade to regulate Bcl‐2‐associated X protein (Bax) activity . PUMA‐deficient colorectal cancer cells eliminate mitochondrial apoptosis caused by various stimuli . However, overexpression of PUMA accelerates apoptosis in various cancer cells …”

Section: Introductionmentioning

confidence: 99%

Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

et al. 2018

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Purified vitexin compound 1 (VB1, a neolignan isolated and extracted from the seed of Chinese herb Vitex negundo) is an effective antitumor agent and exhibits promising clinical activity against various cancers including colorectal cancer. However, it remains unknown about the precise underlying mechanism associated with the antitumor effect of VB1 and how it triggers apoptosis in cancer cells. Here, we demonstrated that VB1 promoted apoptosis via p53‐dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax (Bcl‐2‐associated X protein) activation and mitochondrial dysfunction in colon cancer HCT‐116 and LoVo cells. Deficiency in p53, PUMA, or Bax abrogated VB1‐induced apoptosis and promoted cell survival in HCT‐116 cells. Furthermore, the combination of VB1 with chemotherapeutic drugs 5‐fluorouracil (5‐FU) or NVP‐BZE235 resulted in a synergistic antitumor effect via PUMA induction in HCT‐116 cells. VB1 significantly suppressed the cell proliferation of wild‐type (WT) HCT‐116 and LoVo cells in vitro and tumor growth in vivo. The results indicate that p53/PUMA/Bax axis plays a critical role in VB1‐induced apoptosis and VB1 may have valuable clinical applications in cancer therapy as a novel anticancer agent used alone or in combination with other chemotherapeutic drugs.

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“…BIM is the essential protein that promotes cell death [ 9 , 10 ]. By combining with members of the pro-survival Bcl-2 subfamily, BIM promotes cell apoptosis [ 11 , 12 ]. Moreover, BIM is of vital importance for cell apoptosis which induced by EGFRTKIs in NSCLC patients expressing EGFR mutant [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

et al. 2017

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12.24%). Median progression-free and overall survival was markedly shorter in patients with BIM deletion polymorphism than with BIM wide-type. Moreover, NSCLC cells expressing EGFR-mutant harboring BIM polymorphism were more resistant to erlotinib-induced apoptosis than BIM wide-type cells. However, combined use of erlotinib and the BH3-mimetic ABT-737 up-regulated BIM expression and overcame erlotinib resistance in EGFR-mutant NSCLC cells harboring BIM deletion polymorphism. In vivo, erlotinib suppressed growth of BIM wide-type NSCLC cell xenographs by inducing apoptosis. Combined with ABT-737, erlotinib also suppressed NSCLC xenographs expressing EGFR-mutant harboring BIM deletion polymorphism. These results indicate that BIM polymorphism is closely related to a poor clinical response to EGFR TKIs in EGFR-mutant NSCLC patients, and that the BH3-mimetic ABT-737 restores BIM functionality and EGFR-TKI sensitivity.

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Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation

Cited by 9 publications

References 40 publications

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

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