Ferroptosis, a new form of cell death: opportunities and challenges in cancer

Mou, Yanhua; Wang, Jun; Wu, Jinchun; He, Dan; Zhang, Chunfang; Duan, Chaojun; Li, Bin

doi:10.1186/s13045-019-0720-y

Cited by 1,161 publications

(922 citation statements)

References 112 publications

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“…Ferroptosis is a mode of programmed cell death that is characterized by an iron-dependent accumulation of lipid peroxides [48]. Interestingly, ferroptosis is considered to be pro-inflammatory and immunogenic, due to release of damage-associated molecular patterns (DAMPs) [67,68]. Hence, besides the direct effects on the tumor cells, artesunate may also support anti-tumor immune responses.…”

Section: Discussionmentioning

confidence: 99%

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Sarma

Willmes

Angerer

et al. 2020

Cancers

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Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate-a drug used to treat malaria-has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.Cancers 2020, 12, 919 2 of 15 cells [6], and subsequent studies confirmed that approximately 80% of all MCC cases are associated with MCPyV [7]. Importantly, the integration patterns suggest that clonal expansion of the tumor cells occurs after MCPyV integration sustaining the assumption that viral proteins are causal for tumorigenesis [6,8,9]. Moreover, in MCPyV-positive MCC cells, expression of the viral oncoproteins small and Large T-antigen (sT and LT) can be detected, and these proteins are essential for growth of the tumor cells [10,11] qualifying them as potential therapeutic targets.The five-year overall survival rate for patients with MCC is only about 40%, although the relative survival rate (compared to an age-and sex-matched population) is 54% [12]. Primary MCCs are excised by surgery, and adjuvant radiotherapy of the primary tumor location and the lymph node region is recommended [13]. Until recently, the metastatic disease was treated preferentially with various, not-standardized chemotherapeutic regimens, all of which could not improve survival of the patients significantly [14]. Recently, however, antibodies targeting the immune suppressive protein programmed cell death protein 1 (PD-1) or its ligand PD-L1 have demonstrated high response rates of 56 in first-line and 32% in second-line treatment, respectively for patients with stage IV disease [15,16]. Indeed, the PD-L1 targeting antibody Avelumab was the first treatment for metastatic MCC approved both in the US and European Union [17]. Importantly, data avail...

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Section: Discussionmentioning

confidence: 99%

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Sarma

Willmes

Angerer

et al. 2020

Cancers

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“…A crucial regulator of ferroptosis is the glutathione peroxidase 4 (GPX4), which neutralizes lipids derived from cellular metabolism, thus protecting the cells. The direct or indirect inhibition of GPX4 can cause ferroptosis that promotes the antitumor activity of some tumor suppressors (p53, PTEN, pRb) [68]. Even if cancer cells undergo a high oxidative stress maintaining a balanced level of iron, ferroptosis does not often happen in the cancer development.…”

Section: The Role Of Iron In Oxidative Stressmentioning

confidence: 99%

“…The ROS-and iron-overload cell death became a new target of therapeutic strategy in several disease, including cancer. Indeed, it has been shown that some ferroptosis-inducing agents, such as erastin or sorafenib, have anti-tumor activity [68].…”

Section: The Role Of Iron In Oxidative Stressmentioning

confidence: 99%

Iron Metabolism in Cancer Progression

Forciniti

Greco

Grizzi

et al. 2020

IJMS

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Iron is indispensable for cell metabolism of both normal and cancer cells. In the latter, several disruptions of its metabolism occur at the steps of tumor initiation, progression and metastasis. Noticeably, cancer cells require a large amount of iron, and exhibit a strong dependence on it for their proliferation. Numerous iron metabolism-related proteins and signaling pathways are altered by iron in malignancies, displaying the pivotal role of iron in cancer. Iron homeostasis is regulated at several levels, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Mutations in HFE gene alter iron homeostasis leading to hereditary hemochromatosis and to an increased cancer risk because the accumulation of iron induces oxidative DNA damage and free radical activity. Additionally, the iron capability to modulate immune responses is pivotal in cancer progression. Macrophages show an iron release phenotype and potentially deliver iron to cancer cells, resulting in tumor promotion. Overall, alterations in iron metabolism are among the metabolic and immunological hallmarks of cancer, and further studies are required to dissect how perturbations of this element relate to tumor development and progression.

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“…Emerging evidence indicated that ferroptosis might be an adaptive process to remove carcinogenic cells [7, 8]. Several modulators of ferroptosis have been linked to certain tumors [9]. Glutathioneperoxidase-4 acts as a key antioxidant in redox regulation, and is a regulator of ferroptosis [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1

Shen

Tian

et al. 2020

Preprint

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Selective-induction of regulated cell death is considered as a useful strategy for developing effective therapies against renal cell carcinoma (RCC). In this study, the role of nuclear factor-E2-related factor 2 (Nrf2) and its downstream genes in erastin-induced ferroptosis of renal carcinoma cells was investigated. Erastin induced endoplasmic reticulum (ER) stress and ferroptosis in renal carcinoma cells (786-0 and Caki-1), which was confirmed by morphological changes, increased lipid oxidation and ferroptosis inhibition. Data obtained from TCGA dataset showed that Nrf2 and heme oxygenase-1 (HO-1) were not only significantly differentially expressed between RCC and normal samples, but also associated with better survival in RCC patients. Moreover, the process of ferroptosis induced by erastin in renal carcinoma cells was accompanied by increased expression of Nrf2 and HO-1. Inhibition of Nrf2 or HO-1 expression enhanced lipid ROS accumulation and ferroptosis. Furthermore, pharmacological activation of HO-1 reversed ferroptosis-sensitizing effect of Nrf2 silencing, thereby clarifying the key role of Nrf2/HO-1 pathway in erastin-induced ferroptosis in renal carcinoma cells. In summary, we identified the role of Nrf2/HO-1 signaling pathway in the protection of renal carcinoma cells from ER stress-related ferroptosis, which indicated that targeting of Nrf2/HO-1 pathway as a viable treatment strategy for RCC. Graphical abstract (supplementary figure):Nrf2 protects against ER stress-related ferroptosis via HO-1 in renal cancer cells.Cystine/glutamate antiporter (SLC7A11) abbreviated as xCT. Mitochondria abbreviated as Mito.

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Ferroptosis, a new form of cell death: opportunities and challenges in cancer

Cited by 1,161 publications

References 112 publications

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Iron Metabolism in Cancer Progression

Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1

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