HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma

Zou, Yilong; Palte, Michael J.; Deik, Amy; Li, Haoxin; Eaton, John K.; Wang, Wenyu; Tseng, Yuen-Yi; Deasy, Rebecca; Alimova, Maria; Dančík, Vlado; Leshchiner, Elizaveta S.; Viswanathan, Vasanthi S.; Signoretti, Sabina; Choueiri, Toni K.; Boehm, Jesse S.; Wagner, Bridget K.; Doench, John G.; Clish, Clary B.; Clemons, Paul A.; Schreiber, Stuart L.

doi:10.1101/388041

Cited by 21 publications

(25 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…40 In addition, other studies report that free polyunsaturated fatty acids such as FA (20:4) levels in ccRCC are strongly dependent on hypoxia-inducible factor 2α (HIF-2α) activity. 41 HIF-2α controls the fate of fatty acids either in phospholipid synthesis or in storage to form lipid droplets. 42 We observed elevated levels of PGs and PIs and suppressed aminophospholipids such as PSs and PEs.…”

Section: Discussionmentioning

confidence: 99%

Identification of diagnostic metabolic signatures in clear cell renal cell carcinoma using mass spectrometry imaging

Vijayalakshmi

Shankar

Bain

et al. 2020

Intl Journal of Cancer

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. Intraoperative frozen section (IFS) analysis is used to confirm the diagnosis during partial nephrectomy. However, surgical margin evaluation using IFS analysis is time consuming and unreliable, leading to relatively low utilization. In our study, we demonstrated the use of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) as a molecular diagnostic and prognostic tool for ccRCC. DESI-MSI was conducted on fresh-frozen 23 normal tumor paired nephrectomy specimens of ccRCC. An independent validation cohort of 17 normal tumor pairs was analyzed. DESI-MSI provides two-dimensional molecular images of tissues with mass spectra representing small metabolites, fatty acids and lipids. These tissues were subjected to histopathologic evaluation. A set of metabolites that distinguish ccRCC from normal kidney were identified by performing least absolute shrinkage and selection operator (Lasso) and log-ratio Lasso analysis. Lasso analysis with leave-one-patient-out crossvalidation selected 57 peaks from over 27,000 metabolic features across 37,608 pixels obtained using DESI-MSI of ccRCC and normal tissues. Baseline Lasso of metabolites predicted the class of each tissue to be normal or cancerous tissue with an accuracy of 94 and 76%, respectively. Combining the baseline Lasso with the ratio of glucose to arachidonic acid could potentially reduce scan time and improve accuracy to identify normal (82%) and ccRCC (88%) tissue. DESI-MSI allows rapid detection of metabolites associated with normal and ccRCC with high accuracy. As this technology advances, it could be used for rapid intraoperative assessment of surgical margin status.K.V.L. and V.S. contributed equally to this work Ryan M. Bain's current address is: Dow Chemical Co., Midland, MI 48674 Additional Supporting Information may be found in the online version of this article.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of diagnostic metabolic signatures in clear cell renal cell carcinoma using mass spectrometry imaging

Vijayalakshmi

Shankar

Bain

et al. 2020

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…HIF1 or HIF2 regulates many genes involved in iron homeostasis, such as TFRC, SLC11A2, SLC40A1, CP, HMOX1, and HAMP. Stabilizing HIF1A by hypoxia or cobalt chloride inhibits ferroptosis (Yang et al, 2019), whereas endothelial PAS domain protein 1 (EPAS1/HIF2A) promotes ferroptosis in certain cancer cells (Zou et al, 2019). However, the key downstream genes (not limited to iron metabolism) responsible for HIF-mediated regulation of ferroptosis still need to be further researched.…”

Section: Transcription Factorsmentioning

confidence: 99%

Iron Metabolism in Ferroptosis

Chen

Kang

et al. 2020

Front. Cell Dev. Biol.

594

382

View full text Add to dashboard Cite

Ferroptosis is a form of regulated cell death that is characterized by iron-dependent oxidative damage and subsequent plasma membrane ruptures and the release of damage-associated molecular patterns. Due to the role of iron in mediating the production of reactive oxygen species and enzyme activity in lipid peroxidation, ferroptosis is strictly controlled by regulators involved in many aspects of iron metabolism, such as iron uptake, storage, utilization, and efflux. Translational and transcriptional regulation of iron homeostasis provide an integrated network to determine the sensitivity of ferroptosis. Impaired ferroptosis is implicated in various iron-related pathological conditions or diseases, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. Understanding the molecular mechanisms underlying the regulation of iron metabolism during ferroptosis may provide effective strategies for the treatment of ferroptosis-associated diseases. Indeed, iron chelators effectively prevent the occurrence of ferroptosis, which may provide new approaches for the treatment of iron-related disorders. In this review, we summarize recent advances in the theoretical modeling of iron-dependent ferroptosis, and highlight the therapeutic implications of iron chelators in diseases.

show abstract

“…Actually, the investigation of ferroptosis derives from the studies aiming to identify small molecules that are selectively toxic to oncogenic RAS, which accounts for cancer growth, invasion, and metastasis . Some highly aggressive malignancies have been identified to be vulnerable to ferroptosis intrinsically . Due to its non‐apoptotic nature, ferroptosis‐based cancer therapy is expected to bypass the drawbacks of traditional therapeutics mediated by apoptosis pathways.…”

Section: Introductionmentioning

confidence: 99%

Recent Progress in Ferroptosis Inducers for Cancer Therapy

et al. 2019

View full text Add to dashboard Cite

Ferroptosis is a newly discovered form of regulated cell death that is the nexus between metabolism, redox biology, and human health. Emerging evidence shows the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Recently, there has been a great deal of effort to design and develop anticancer drugs based on ferroptosis induction. Recent advances of ferroptosis‐inducing agents at the intersection of chemistry, materials science, and cancer biology are presented. The basis of ferroptosis is summarized first to highlight the feasibility and characteristics of triggering ferroptosis for cancer therapy. A literature review of ferroptosis inducers (including small molecules and nanomaterials) is then presented to delineate their design, action mechanisms, and anticancer applications. Finally, some considerations for research on ferroptosis inducers are spotlighted, followed by a discussion on the challenges and future development directions of this burgeoning field.

show abstract

HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma

Cited by 21 publications

References 110 publications

Identification of diagnostic metabolic signatures in clear cell renal cell carcinoma using mass spectrometry imaging

Identification of diagnostic metabolic signatures in clear cell renal cell carcinoma using mass spectrometry imaging

Iron Metabolism in Ferroptosis

Recent Progress in Ferroptosis Inducers for Cancer Therapy

Contact Info

Product

Resources

About