ent-Kaurane diterpenoids induce apoptosis and ferroptosis through targeting redox resetting to overcome cisplatin resistance

Sun, Yong; Qiao, Yanan; Liu, Yue; Zhou, Jinchuan; Wang, Xue; Zheng, Hongbo; Xu, Zejun; Zhang, Jiaozhen; Zhou, Yi; Qian, Lilin; Zhang, Chunyang; Lou, Hongxiang

doi:10.1016/j.redox.2021.101977

Cited by 61 publications

(40 citation statements)

References 56 publications

(59 reference statements)

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“… 11 , 12 Moreover, induction of ferroptosis enhances the therapeutic efficacy of cisplatin in cancer cells. 13 , 14 In the context of PCa, tumor cells are vulnerable to ferroptosis induction, and treatment with the antiandrogen enzalutamide induces lipid peroxidation and leads to sensitivity to GPX4 inhibition and ferroptosis. 4 , 15 Therefore, ferroptosis is closely related to PCa progression, and ferroptosis inducers may be even more potent in combination therapy settings.…”

Section: Introductionmentioning

confidence: 99%

ATF6α promotes prostate cancer progression by enhancing PLA2G4A‐mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis

Zhao

Feng

et al. 2022

The Prostate

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Background Despite the clinical success of androgen receptor (AR)‐targeted therapies, prostate cancer (PCa) inevitably progresses to castration‐resistant prostate cancer (CRPC). Transcription factor 6 α (ATF6α), an effector of the unfolded protein response (UPR) that modulates the cellular response to endoplasmic reticulum (ER) stress, has been linked to tumor development, metastasis, and relapse. However, the role of ATF6α in CRPC remains unclear. Methods The effect of ATF6α on the CRPC‐like phenotype in PCa cells was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)−5‐(3‐carb‐Oxymethoxyphenyl)−2‐(4‐sulfophenyl)−2H‐tetrazolium inner salt (MTS), 5‐Bromo‐2‐deoxyUridine (BrdU) incorporation analysis, and cell death assay. Mechanistically, bioinformatic analysis was utilized to evaluate the potential of PLA2G4A as the target of ATF6α. Moreover, Western blot analysis, real‐time polymerase chain reaction, chromatin immunoprecipitation, arachidonic acid (AA), and prostaglandin E2 (PGE2) assays were performed to identify the regulatory effect of ATF6α on PLA2G4A. Results In this study, we found that the increase of ATF6α expression in response to androgen deprivation generates PCa cells with a CRPC‐like phenotype. PCa cells with high levels of ATF6α expression are resistant to ferroptosis, and genetic and pharmacological inhibition of ATF6α could, therefore, promote the ferroptotic death of tumor cells and delay PCa progression. Molecular analyses linked ATF6α regulation of ferroptosis to the PLA2G4A‐mediated release of AA and the resulting increase in PGE2 production, the latter of which acts as an antiferroptotic factor. Conclusions This study defines ATF6α as a novel antiferroptotic regulator that exacerbates PCa progression. In addition, our data establish ATF6α‐PLA2G4A signaling as an important pathological pathway in PCa, and targeting this pathway may be a novel treatment strategy.

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Section: Introductionmentioning

confidence: 99%

ATF6α promotes prostate cancer progression by enhancing PLA2G4A‐mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis

Zhao

Feng

et al. 2022

The Prostate

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“…ATF3 (activating transcription factor 3) may induce ferroptosis by blocking the Nrf2/Keap1/xCT signaling pathway and reverse the sensitivity of gastric cancer cells to cisplatin ( Fu D. et al, 2021 ). Ent-Kaurane derivatives are promising in chemotherapy and are capable of reversing the resistance to cisplatin by dual inhibition of PRDX I/II and GSH ( Sun Y. et al, 2021 ). Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases ( Ferlay et al, 2015 ).…”

Section: Ferroptosis and Drug Resistancementioning

confidence: 99%

Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer

Zhang

et al. 2022

Front. Pharmacol.

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Ferroptosis is an iron-dependent regulated form of cell death caused by excessive lipid peroxidation. This form of cell death differed from known forms of cell death in morphological and biochemical features such as apoptosis, necrosis, and autophagy. Cancer cells require higher levels of iron to survive, which makes them highly susceptible to ferroptosis. Therefore, it was found to be closely related to the progression, treatment response, and metastasis of various cancer types. Numerous studies have found that the ferroptosis pathway is closely related to drug resistance and metastasis of cancer. Some cancer cells reduce their susceptibility to ferroptosis by downregulating the ferroptosis pathway, resulting in resistance to anticancer therapy. Induction of ferroptosis restores the sensitivity of drug-resistant cancer cells to standard treatments. Cancer cells that are resistant to conventional therapies or have a high propensity to metastasize might be particularly susceptible to ferroptosis. Some biological processes and cellular components, such as epithelial–mesenchymal transition (EMT) and noncoding RNAs, can influence cancer metastasis by regulating ferroptosis. Therefore, targeting ferroptosis may help suppress cancer metastasis. Those progresses revealed the importance of ferroptosis in cancer, In order to provide the detailed molecular mechanisms of ferroptosis in regulating therapy resistance and metastasis and strategies to overcome these barriers are not fully understood, we described the key molecular mechanisms of ferroptosis and its interaction with signaling pathways related to therapy resistance and metastasis. Furthermore, we summarized strategies for reversing resistance to targeted therapy, chemotherapy, radiotherapy, and immunotherapy and inhibiting cancer metastasis by modulating ferroptosis. Understanding the comprehensive regulatory mechanisms and signaling pathways of ferroptosis in cancer can provide new insights to enhance the efficacy of anticancer drugs, overcome drug resistance, and inhibit cancer metastasis.

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“… [ 34 ] Cisplatin Ent-kaurane diterpenoids Glutathione (GSH) Lung cancer Ent-kaurane diterpenoids target peroxiredoxin I/II and block GSH synthesis, thereby inducing ferroptosis and overcoming cisplatin resistance. [ 35 ] Erastin and sulfasalazine Cystine/glutamate antiporter (xCT) Head and neck cancer Erastin and sulfasalazine inhibit the xCT system to induce ferroptosis and overcome cisplatin resistance. [ 36 ] / xCT Gastric cancer Suppressing the Nrf2/Keap1/xCT pathway inhibits xCT system to induce ferroptosis and overcome cisplatin resistance.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, ent-kaurane diterpenoids have been reported to be able to overcome cisplatin resistance by inducing ferroptosis. Further mechanistic studies have revealed that ferroptosis induced by ent-kaurane diterpenoids is caused by targeting peroxiredoxin I/II and depleting GSH [ 35 ]. Cysteine is an essential cellular antioxidant and the rate-limiting amino acid for GSH biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis in cancer therapy: a novel approach to reversing drug resistance

et al. 2022

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Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus providing new opportunities for cancer therapy. The development of resistance to cancer therapy remains a major challenge. A number of preclinical and clinical studies have focused on overcoming drug resistance. Intriguingly, ferroptosis has been correlated with cancer therapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. Herein, we provide a detailed description of the mechanisms of ferroptosis and the therapeutic role of regulating ferroptosis in reversing the resistance of cancer to common therapies, such as chemotherapy, targeted therapy and immunotherapy. We discuss the prospect and challenge of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance and expect that our review could provide some references for further studies.

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ent-Kaurane diterpenoids induce apoptosis and ferroptosis through targeting redox resetting to overcome cisplatin resistance

Cited by 61 publications

References 56 publications

ATF6α promotes prostate cancer progression by enhancing PLA2G4A‐mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis

ATF6α promotes prostate cancer progression by enhancing PLA2G4A‐mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis

Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer

Ferroptosis in cancer therapy: a novel approach to reversing drug resistance

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