The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine

Chidley, Christopher; Trauger, Sunia A.; Birsoy, Kıvanç; O’Shea, Erin K.

doi:10.7554/elife.14601

Cited by 55 publications

(52 citation statements)

References 64 publications

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“…Disorders in PE metabolism have been implicated in many chronic diseases, such as Alzheimer's disease, Parkinson's disease, and nonalcoholic liver disease [82], as well as metabolic disorders such as atherosclerosis, insulin resistance, and obesity [63]. Increased levels of PE have been described in cancer cells leading to PE being regarded as a target in the development of anticancer therapies [83].…”

Section: Phosphatidylethanolamine and Its Physiological Functionsmentioning

confidence: 99%

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Pohl

Jovanović

2019

Molecules

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Reactive oxygen species (ROS) and their derivatives, reactive aldehydes (RAs), have been implicated in the pathogenesis of many diseases, including metabolic, cardiovascular, and inflammatory disease. Understanding how RAs can modify the function of membrane proteins is critical for the design of therapeutic approaches in the above-mentioned pathologies. Over the last few decades, direct interactions of RA with proteins have been extensively studied. Yet, few studies have been performed on the modifications of membrane lipids arising from the interaction of RAs with the lipid amino group that leads to the formation of adducts. It is even less well understood how various multiple adducts affect the properties of the lipid membrane and those of embedded membrane proteins. In this short review, we discuss a crucial role of phosphatidylethanolamine (PE) and PE-derived adducts as mediators of RA effects on membrane proteins. We propose potential PE-mediated mechanisms that explain the modulation of membrane properties and the functions of membrane transporters, channels, receptors, and enzymes. We aim to highlight this new area of research and to encourage a more nuanced investigation of the complex nature of the new lipid-mediated mechanism in the modification of membrane protein function under oxidative stress.

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Section: Phosphatidylethanolamine and Its Physiological Functionsmentioning

confidence: 99%

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Pohl

Jovanović

2019

Molecules

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“…Natural products represent a rich source for small molecule therapeutics; however, the molecular targets of these compounds are often elusive. [45][46][47][48] CWO presents challenges for identifying the precise molecular target due to the complexity of the admixture and potentially combinatorial effects of the terpene constituents. CWO stimulated calcium signaling in keratinocytes, followed by NFAT translocation to the nucleus ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Camphor white oil induces tumor regression through cytotoxic T cell‐dependent mechanisms

Moayedi

Greenberg

Jenkins

et al. 2019

Molecular Carcinogenesis

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Bioactive derivatives from the camphor laurel tree, Cinnamomum camphora, are posited to exhibit chemopreventive properties but the efficacy and mechanism of these natural products are not fully understood. We tested an essential‐oil derivative, camphor white oil (CWO), for anti‐tumor activity in a mouse model of keratinocyte‐derived skin cancer. Daily topical treatment with CWO induced dramatic regression of pre‐malignant skin tumors and a two‐fold reduction in cutaneous squamous cell carcinomas. We next investigated underlying cellular and molecular mechanisms. In cultured keratinocytes, CWO stimulated calcium signaling, resulting in calcineurin‐dependent activation of nuclear factor of activated T cells (NFAT). In vivo, CWO induced transcriptional changes in immune‐related genes identified by RNA‐sequencing, resulting in cytotoxic T cell‐dependent tumor regression. Finally, we identified chemical constituents of CWO that recapitulated effects of the admixture. Together, these studies identify T cell‐mediated tumor regression as a mechanism through which a plant‐derived essential oil diminishes established tumor burden.

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“…A recent study has found that a natural product, ophiobolin A (OPA) exerts its cytotoxicity toward cancer cells by forming a pyrrole-containing covalent cytotoxic adduct with the ethanolamine head group of PE, subsequently leading to lipid bilayer destabilization (Chidley et al, 2016). OPA is a plant toxin isolated from pathogenic fungi of the Bipolaris genus that exhibits cytotoxicity at nanomolar concentrations against a range of cancer cell lines.…”

Section: Phosphatidylethanolamine As An Anti-cancer Targetmentioning

confidence: 99%

“…OPA is a plant toxin isolated from pathogenic fungi of the Bipolaris genus that exhibits cytotoxicity at nanomolar concentrations against a range of cancer cell lines. Basically, the study performed an unbiased genome-wide approach to identify the molecular target of OPA through insertional mutagenesis of near-haploid cell line KBM7 using retroviral gene trap approach and demonstrated that OPA forms PE-OPA adducts associated with membrane disruption and eventual cell death (Chidley et al, 2016). This discovery highlighted the potential importance of PE as the molecular target for small molecules which provides further impetus to pursue targeting PE as a novel chemotherapeutic approach, particularly against cancer types which are known to respond poorly to current chemotherapy.…”

Section: Phosphatidylethanolamine As An Anti-cancer Targetmentioning

confidence: 99%

Targeting Membrane Lipid a Potential Cancer Cure?

et al. 2017

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Cancer mortality and morbidity is projected to increase significantly over the next few decades. Current chemotherapeutic strategies have significant limitations, and there is great interest in seeking novel therapies which are capable of specifically targeting cancer cells. Given that fundamental differences exist between the cellular membranes of healthy cells and tumor cells, novel therapies based on targeting membrane lipids in cancer cells is a promising approach that deserves attention in the field of anticancer drug development. Phosphatidylethanolamine (PE), a lipid membrane component which exists only in the inner leaflet of cell membrane under normal circumstances, has increased surface representation on the outer membrane of tumor cells with disrupted membrane asymmetry. PE thus represents a potential chemotherapeutic target as the higher exposure of PE on the membrane surface of cancer cells. This feature as well as a high degree of expression of PE on endothelial cells in tumor vasculature, makes PE an attractive molecular target for future cancer interventions. There have already been several small molecules and membrane-active peptides identified which bind specifically to the PE molecules on the cancer cell membrane, subsequently inducing membrane disruption leading to cell lysis. This approach opens up a new front in the battle against cancer, and is of particular interest as it may be a strategy that may be prove effective against tumors that respond poorly to current chemotherapeutic agents. We aim to highlight the evidence suggesting that PE is a strong candidate to be explored as a potential molecular target for membrane targeted novel anticancer therapy.

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The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine

Cited by 55 publications

References 64 publications

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Camphor white oil induces tumor regression through cytotoxic T cell‐dependent mechanisms

Targeting Membrane Lipid a Potential Cancer Cure?

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