Read by QxMD icon Read


Tanja Krainz, Michael M Gaschler, Chaemin Lim, Joshua R Sacher, Brent R Stockwell, Peter Wipf
Discovering compounds and mechanisms for inhibiting ferroptosis, a form of regulated, nonapoptotic cell death, has been of great interest in recent years. In this study, we demonstrate the ability of XJB-5-131, JP4-039, and other nitroxide-based lipid peroxidation mitigators to prevent ferroptotic cell death in HT-1080, BJeLR, and panc-1 cells. Several analogues of the reactive oxygen species (ROS) scavengers XJB-5-131 and JP4-039 were synthesized to probe structure-activity relationships and the influence of subcellular localization on the potency of these novel ferroptosis suppressors...
September 28, 2016: ACS Central Science
Shang-Jui Wang, Dawei Li, Yang Ou, Le Jiang, Yue Chen, Yingming Zhao, Wei Gu
Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53(K98R)) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p53(4KR): K98R+ 3KR[K117R+K161R+K162R]) completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11...
October 4, 2016: Cell Reports
Yang Ou, Shang-Jui Wang, Dawei Li, Bo Chu, Wei Gu
Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N(1)-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sung Eun Kim, Li Zhang, Kai Ma, Michelle Riegman, Feng Chen, Irina Ingold, Marcus Conrad, Melik Ziya Turker, Minghui Gao, Xuejun Jiang, Sebastien Monette, Mohan Pauliah, Mithat Gonen, Pat Zanzonico, Thomas Quinn, Ulrich Wiesner, Michelle S Bradbury, Michael Overholtzer
The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice...
September 26, 2016: Nature Nanotechnology
Tina Sehm, Manfred Rauh, Kurt Wiendieck, Michael Buchfelder, IIker Y Eyüpoglu, Nicolai E Savaskan
The glutamate exchanger xCT (SLC7a11) is causally linked with the malignancy grade of brain tumors and represents a key player in glutamate, cystine and glutathione metabolism. Although blocking xCT is not cytotoxic for brain tumors, xCT inhibition disrupts the neurodegenerative and microenvironment-toxifying activity of gliomas. Here, we report on the use of various xCT inhibitors as single modal drugs and in combination with the autophagy-inducing standard chemotherapeutic agent temozolomide (Temodal/Temcad®, TMZ)...
September 6, 2016: Oncotarget
Hua Yuan, Xuemei Li, Xiuying Zhang, Rui Kang, Daolin Tang
Ferroptosis, a recently identified form of non-apoptotic cell death, is involved in several physiological and pathological processes. Although lipid peroxidation plays a central role in triggering ferroptosis, the essential regulator of lipid metabolism in ferroptosis remains poorly defined. Here, we show that acyl-CoA synthetase long-chain family member 4 (ACSL4) is required for ferroptotic cancer cell death. Compared with ferroptosis-sensitive cells (e.g., HepG2 and HL60), the expression of ACSL4 was remarkably downregulated in ferroptosis-resistant cells (e...
September 23, 2016: Biochemical and Biophysical Research Communications
Minghui Gao, Prashant Monian, Qiuhui Pan, Wei Zhang, Jenny Xiang, Xuejun Jiang
Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4...
September 2016: Cell Research
Hua Yuan, Xuemei Li, Xiuying Zhang, Rui Kang, Daolin Tang
Ferroptosis is a form of non-apoptotic cell death originally identified in cancer cells. However, the key regulator of ferroptosis in mitochondria remains unknown. Here, we show that CDGSH iron sulfur domain 1 (CISD1, also termed mitoNEET), an iron-containing outer mitochondrial membrane protein, negatively regulates ferroptotic cancer cell death. The classical ferroptosis inducer erastin promotes CISD1 expression in an iron-dependent manner in human hepatocellular carcinoma cells (e.g., HepG2 and Hep3B). Genetic inhibition of CISD1 increased iron-mediated intramitochondrial lipid peroxidation, which contributes to erastin-induced ferroptosis...
September 16, 2016: Biochemical and Biophysical Research Communications
Wan Seok Yang, Katherine J Kim, Michael M Gaschler, Milesh Patel, Mikhail S Shchepinov, Brent R Stockwell
Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown...
August 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
Renyu Lin, Ziheng Zhang, Lingfeng Chen, Yunfang Zhou, Peng Zou, Chen Feng, Li Wang, Guang Liang
Head and neck cancer is the sixth most common cancer worldwide. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, exhibits a wide range of biological roles including a highly efficient and specific anti-tumor activity. Here, we aimed to examine the effect of DHA on head and neck carcinoma cells and elucidate the potential mechanisms. We used five head and neck carcinoma cell lines and two non-tumorigenic normal epithelial cell lines to achieve our goals. Cells were exposed to DHA and subjected to cellular activity assays including viability, cell cycle analysis, cell death, and angiogenic phenotype...
October 10, 2016: Cancer Letters
Jong-Lyel Roh, Eun Hye Kim, Hye Jin Jang, Jin Young Park, Daiha Shin
Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy-resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models...
October 10, 2016: Cancer Letters
S Ma, E S Henson, Y Chen, S B Gibson
Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, siramesine and a tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24 h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with siramesine and lapatinib...
2016: Cell Death & Disease
Britt Hanson
This review embarks upon a cell death journey from the discovery of apoptosis and necrosis through to the coalescence of these: necroptosis. The mechanisms of 2 emerging necrotic cell death pathways, pyroptosis and ferroptosis, will be explored before delving into apoptotic and necroptotic signaling cascades, highlighting the complex interplay between molecular players. The involvement of the ripoptosome, interferon signaling and DNA damage in necroptosis will be discussed briefly. The major focus is on necroptosis initiation by tumor necrosis factor-α (TNFα) and its cognate receptor TNFR1, caspase-independent RIP1/RIP3/MLKL necrosome activation and cell death propagation by damage-associated molecular pattern (DAMP) release...
September 2016: Cancer Biology & Therapy
Xinlei Yu, Yun Chau Long
Although essential amino acids regulate mechanistic target of rapamycin complex 1 (mTORC1) and the integrated stress response (ISR), the role of cysteine is unknown. We found that in hepatoma HepG2 cells, cystine (oxidized form of cysteine) activated mTORC1 and suppressed the ISR. Cystine deprivation induced GSH efflux and extracellular degradation, which aimed to restore cellular cysteine. Inhibition of γ-glutamyl transpeptidase (GGT) impaired the ability of GSH or cell-permeable GSH to restore mTORC1 signaling and the ISR, suggesting that the capacity of GSH to release cysteine, but not GSH per se, regulated the signaling networks...
2016: Scientific Reports
Takashi Kasukabe, Yoshio Honma, Junko Okabe-Kado, Yusuke Higuchi, Nobuo Kato, Shunichi Kumakura
The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines. In the present study, we demonstrated that CN-A and phenethyl isothiocyanate (PEITC), an inducer of reactive oxygen species (ROS) and a dietary anticarcinogenic compound, synergistically inhibited the proliferation of MIAPaCa-2, PANC-1 and gemcitabine-resistant PANC-1 cells...
August 2016: Oncology Reports
Bowen Ke, Mao Tian, Jingjing Li, Bo Liu, Gu He
Evasion of cell death is one of the hallmarks of cancer cells, beginning with long-established apoptosis and extending to other new forms of cell death. An elaboration of cell death pathways thus will contribute to a better understanding of cancer pathogenesis and therapeutics. With the recent substantial biochemical and genetic explorations of cell death subroutines, their classification has switched from primarily morphological to more molecular definitions. According to their measurable biochemical features and intricate mechanisms, cell death subroutines can be divided into apoptosis, autophagic cell death, mitotic catastrophe, necroptosis, parthanatos, ferroptosis, pyroptosis, pyronecrosis, anoikis, cornification, entosis, and NETosis...
June 30, 2016: Medicinal Research Reviews
Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Susana Carrasco, Pablo Cannata-Ortiz, Maria D Sanchez-Niño, Marta Ruiz Ortega, Jesus Egido, Andreas Linkermann, Alberto Ortiz, Ana B Sanz
AKI is histologically characterized by necrotic cell death and inflammation. Diverse pathways of regulated necrosis have been reported to contribute to AKI, but the molecular regulators involved remain unclear. We explored the relative contributions of ferroptosis and necroptosis to folic acid (FA)-induced AKI in mice. FA-AKI in mice associates with lipid peroxidation and downregulation of glutathione metabolism proteins, features that are typical of ferroptotic cell death. We show that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, preserved renal function and decreased histologic injury, oxidative stress, and tubular cell death in this model...
June 27, 2016: Journal of the American Society of Nephrology: JASN
Jay P Garg, Domagoj Vucic
Precise regulation of cell death and survival is essential for proper maintenance of organismal homeostasis, development, and the immune system. Deregulated cell death can lead to developmental defects, neuropathies, infections, and cancer. Kidney diseases, especially acute pathologies linked to ischemia-reperfusion injury, are among illnesses that profoundly are affected by improper regulation or execution of cell death pathways. Attempts to develop medicines for kidney diseases have been impacted by the complexity of these pathologies given the heterogeneous patient population and diverse etiologies...
May 2016: Seminars in Nephrology
Jesper Kers, Jaklien C Leemans, Andreas Linkermann
Necrosis is the predominant form of regulated cell death in acute kidney injury (AKI) and represents results in the formation of casts that appear in the urine sedimentation, referred to as muddy brown casts, which are part of the diagnosis of AKI. Pathologists referred to this typical feature as acute tubular necrosis. We are only beginning to understand the dynamics and the molecular pathways that underlie such typical necrotic morphology. In this review, we provide an overview of candidate pathways and summarize the emerging evidence for the relative contribution of these pathways of regulated necrosis, such as necroptosis, ferroptosis, mitochondrial permeability transition-mediated regulated necrosis, parthanatos, and pyroptosis...
May 2016: Seminars in Nephrology
Shang-Jui Wang, Yang Ou, Le Jiang, Wei Gu
Recent evidence indicates that canonical functions of p53 (i.e., apoptosis and growth arrest) are dispensable for p53-mediated tumor suppression. We have uncovered a novel function of p53 that contributes to tumor suppression through regulation of cystine metabolism, reactive oxygen species responses, and ferroptosis. The p53-mediated ferroptotic response via SLC7A11 denotes an extra layer of defense against tumorigenesis in conjunction with other p53 functions.
May 2016: Molecular & Cellular Oncology
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"