ΔNp63 Inhibits Oxidative Stress-Induced Cell Death, Including Ferroptosis, and Cooperates with the BCL-2 Family to Promote Clonogenic Survival

Wang, Gary X.; Tu, Ho Chou; Dong, Yiyu; Skanderup, Anders Jacobsen; Wang, Yufeng; Takeda, Shugaku; Ganesan, Yogesh Tengarai; Han, Song Iy; Han, Liang; Hsieh, James J.; Cheng, Emily H.

doi:10.1016/j.celrep.2017.11.030

Cited by 70 publications

(67 citation statements)

References 49 publications

(79 reference statements)

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“…Given the possibility that CSCs would be more resistant to chemotherapy due to upregulated antiredox mechanisms (11) and considering a recently proposed association between oxidative stress and ferroptosis, a new form of cell death triggered by oxidized lipids, we examined a gene set related to "ferroptosis" (24) in platinum tolerant compared to parental OC cells. Clear differences including upregulated genes involved in glutathione metabolism and anti-oxidant defense mechanisms were observed in platinum-tolerant OC cells vs. chemotherapy-naïve cells (SKOV3,…”

Section: Stemness and Ferroptosis Signatures Are Enriched In Platinummentioning

confidence: 99%

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

“…GPX4 participates in regulation of intra-cellular redox states by utilizing glutathione (GSH) as the critical antioxidant (24). GSH is synthesized from glutamate-cysteine under the action of glutamate-cysteine ligase (GCL) (24). The cycling of reduced GSH to oxidized glutathione disulfide (GSSG) removes ROS derived from hydrogen peroxide and lipid hydroperoxides through various glutathione peroxidases (GPXs), including GPX4 (24).…”

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

“…GSH is synthesized from glutamate-cysteine under the action of glutamate-cysteine ligase (GCL) (24). The cycling of reduced GSH to oxidized glutathione disulfide (GSSG) removes ROS derived from hydrogen peroxide and lipid hydroperoxides through various glutathione peroxidases (GPXs), including GPX4 (24). GSH recycling from GSSH is catalyzed by glutathione reductase (GSR), using NADPH, whose synthesis is regulated by isocitrate dehydrogenase 2 (IDH2) (24).…”

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

“…The cycling of reduced GSH to oxidized glutathione disulfide (GSSG) removes ROS derived from hydrogen peroxide and lipid hydroperoxides through various glutathione peroxidases (GPXs), including GPX4 (24). GSH recycling from GSSH is catalyzed by glutathione reductase (GSR), using NADPH, whose synthesis is regulated by isocitrate dehydrogenase 2 (IDH2) (24). FZD7 knockdown in OVCAR5 cells, decreased the expression levels of multiple genes in this pathway, including GPX2, GSS (glutathione synthase), IDH2, GSR, GCLC and SLC7A11 (solute carrier family 7 member 11, cystine/glutamate transporter) (OVCAR5, Fig.…”

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

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Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Wang

Zhao

Condello

et al. 2020

Preprint

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The authors have no conflicts of interest to declare. AbstractDefining traits of platinum tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum tolerant cells and tumors were identified by using in vitro and in vivo ovarian cancer (OC) models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were found to be enriched in ALDH (+) cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared to parental cells. Additionally, platinum-tolerant cells and tumors highly expressed the Wnt receptor, Frizzled 7 (FZD7). FZD7 knock down improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7(+) from FZD7(-) cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protects cells from chemotherapy-induced oxidative stress. FZD7(+) platinum-tolerant OC cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63 and glutathione metabolism gene sets were strongly correlated in the OC Tumor Cancer Genome Atlas (TCGA) database and in human OC specimens residual after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial stem cell features, characterized by FZD7 expression and dependent on FZD7-b-catenin-Tp63-GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype.glutathione peroxidase 4 (GPX4) tumor initiation capacity (TIC) (10). Importantly, ovarian CSCs possess a phenotype associated with drug resistance, including enhanced DNA repair, diminished apoptotic responses, increased efflux mechanisms and enhanced antioxidation defense (8,11), which allow them to escape from chemotherapy. The boundaries between stemness and chemotherapy tolerant phenotypes remain blurry and while an overlap exists, it is assumed that distinct pathways drive the two entities.As platinum tolerant cancer cells drive tumor relapse, decreasing survival rate of women with OC, we aimed to identify specific markers, by using in vitro and in vivo models of repeated exposure to the cytotoxic agent. We observed that platinum-tolerant cells and tumors contained an increased ALDH+ cell population, expressing stemness related transcription factors (TFs), and able to form more spheroids compared to chemotherapy naïve cells. We identified the Frizzled 7 receptor (FZD7) as a novel cell surface marker significantly upregulated in the platinum tolerant cell population. FZD7 knock down increased sensitivity to platinum, decreased spheroid formation in vitro, and delayed tumor initiation in vivo. FZD7...

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Section: Stemness and Ferroptosis Signatures Are Enriched In Platinummentioning

confidence: 99%

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

Section: Molecular Signatures Of Fzd7(+) Cancer Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Wang

Zhao

Condello

et al. 2020

Preprint

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History of IMiDs and Protein Degradation as a Pharmacological Modality

Yamamoto

Asatsuma‐Okumura

Ito

et al. 2022

Protein Homeostasis in Drug Discovery

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RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

Shen

Wen-hai

Bai

et al. 2020

The Anatomical Record

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Resibufogenin (RB) has been used for cancer treatment, but the underlying mechanisms are still unclear. This study aimed to investigate the effects of RB treatment on colorectal cancer (CRC) cells, and to determine the underlying mechanisms. The cell counting kit‐8 assay was used to determine cell viability. Cell morphology was observed under light microscopy, and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling assay was employed to detect cell apoptosis. Intracellular ferrous iron (Fe2+), malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species levels were detected by using commercial iron assay kit, MDA assay kit, GSH assay kit, and 2,7‐dichlorodihydrofluorescein diacetate probes, respectively. The protein expressions were determined by Western blot and immunohistochemistry. RB inhibited cell viability in the CRC cell lines (HT29 and SW480) in a dose‐ and time‐dependent manner, and caused cytotoxicity to the normal colonic epithelial cell line (NCM460) at high dose. Similarly, RB induced morphological changes in CRC cells from normal to round shape, and promoted cell death. Of note, RB triggered oxidative stress and ferroptotic cell death in CRC cells, and only ferroptosis inhibitors (deferoxamine and ferrostatin‐1), instead of inhibitors for other types of cell death (apoptosis, autophagy, and necroptosis), reversed the inhibitory effects of RB on CRC cell proliferation. Furthermore, glutathione peroxidase 4 (GPX4) was inactivated by RB treatment, and overexpression of GPX4 alleviated RB‐induced oxidative cell death in CRC cells. Consistently, the in vivo experiments validated that RB also triggered oxidative stress, and inhibited CRC cells growth and tumorigenicity in mice models. RB can inhibit CRC cells growth and tumorigenesis by triggering ferroptotic cell death in a GPX4 inactivation‐dependent manner.

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ΔNp63 Inhibits Oxidative Stress-Induced Cell Death, Including Ferroptosis, and Cooperates with the BCL-2 Family to Promote Clonogenic Survival

Cited by 70 publications

References 49 publications

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

History of IMiDs and Protein Degradation as a Pharmacological Modality

RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

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