BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance

Kong, Yingyi; Akatsuka, Shinya; Motooka, Yashiro; Zheng, Hao; Cheng, Zhen; Shiraki, Yukihiro; Mashimo, Tomoji; Imaoka, Tatsuhiko; Toyokuni, Shinya

doi:10.1016/j.redox.2022.102356

Cited by 15 publications

(26 citation statements)

References 71 publications

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“…Furthermore, we found that renal cell carcinomas (RCCs) in Brca1 mutants show more genomic alterations, including c-Myc amplification [83], which is indeed frequently observed in the breast carcinoma of human BRCA1 mutants [87] and is a risk for poor prognosis [88,89]. Here c-Myc amplification was often extrachromosomal.…”

Section: Brca1 and Ferroptosis-resistancementioning

confidence: 98%

“…We then undertook to understand the molecular mechanism why iron-catalyzed oxidative stress promotes renal carcinogenesis. We have performed expression microarray analysis in the subacute phase of 3 weeks during the renal carcinogenesis and found that higher mitochondrial damage is a key phenomenon [83]. Electron microscopical analysis revealed that even the untreated control kidney showed smaller and deformed mitochondria in the renal tubular cells of Brca1 mutants.…”

Section: Genetic Alterations By Acghmentioning

confidence: 99%

“…We have recently applied Fe-NTA renal carcinogenesis model to male Brca1(L63X/ +) rats to evaluate whether iron-catalyzed oxidative stress [12] is important for Brca1 mutant carcinogenesis [83]. The incidence of renal carcinogenesis was not changed between the Brca1 mutant and the wild-type.…”

Section: Brca1 and Ferroptosis-resistancementioning

confidence: 99%

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Environmental impact on carcinogenesis under BRCA1 haploinsufficiency

et al. 2023

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Cancer is the primary cause of human mortality in Japan since 1981. Although numerous novel therapies have been developed and applied in clinics, the number of deaths from cancer is still increasing worldwide. It is time to consider the strategy of cancer prevention more seriously. Here we propose a hypothesis that cancer can be side effects of long time-use of iron and oxygen and that carcinogenesis is an evolution-like cellular events to obtain “iron addiction with ferroptosis-resistance” where genes and environment interact each other. Among the recognized genetic risk factors for carcinogenesis, we here focus on BRCA1 tumor suppressor gene and how environmental factors, including daily life exposure and diets, may impact toward carcinogenesis under BRCA1 haploinsufficiency. Although mice models of BRCA1 mutants have not been successful for decades in generating phenotype mimicking the human counterparts, a rat model of BRCA1 mutant was recently established that reasonably mimics the human phenotype. Two distinct categories of oxidative stress, one by radiation and one by iron-catalyzed Fenton reaction, promoted carcinogenesis in Brca1 rat mutants. Furthermore, mitochondrial damage followed by alteration of iron metabolism finally resulted in ferroptosis-resistance of target cells in carcinogenesis. These suggest a possibility that cancer prevention by active pharmacological intervention may be possible for BRCA1 mutants to increase the quality of their life rather than preventive mastectomy and/or oophorectomy.

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Section: Brca1 and Ferroptosis-resistancementioning

confidence: 98%

Section: Genetic Alterations By Acghmentioning

confidence: 99%

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Environmental impact on carcinogenesis under BRCA1 haploinsufficiency

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“…Rat Brca1(L63X/+) provides promotional effect on carcinogenesis through chromosomal amplification and ferroptosis-resistance (151) among the most popular targets in various human cancers. (56,57) Regarding the allelic loss of p16 Ink4a tumor suppressor gene, this phenomenon was frequently observed in many cell lines which were cultured over a long period in the 1990's.…”

Section: Mysterious Link Between P16 and Carcinogenesismentioning

confidence: 99%

Iron as spirit of life to share under monopoly

Toyokuni

Kong

Zheng

et al. 2022

J. Clin. Biochem. Nutr.

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Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multisystem organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.

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“…After the discovery of BRCA1, various murine models were genetically engineered unfortunately with failure 14 . Recently, a Brca1 (L63X/+) rat model was established, which showed significant susceptibility to radiation‐induced breast cancer, 15 as well as to ferric nitrilotriacetate‐induced renal cancer 16–18 . This iron‐dependent carcinogenic process of MM can be mitigated by redox‐inactive iron chelators 19 or phlebotomy 20 .…”

Section: Introductionmentioning

confidence: 99%

BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile‐induced mesothelioma via ferroptosis resistance

et al. 2023

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Malignant mesothelioma (MM) is still a social burden associated with asbestos exposure. Local iron accumulation thereby represents the major pathogenesis, followed by oxidative DNA strand breaks and genomic alterations in the mesothelium. BRCA1 is a critical component of homologous recombination repair directed to DNA double‐stranded breaks, whereas BRCA1 germline mutation is an established risk for breast/ovarian cancer, its role in MM development remains to be elucidated. Murine Brca1 mutant models so far have not reproduced human phenotypes. However, a rat Brca1 mutant model (Mut; L63X/+ ) recently reproduced them at least partially. Here we describe the differential induction of MM in Brca1 mutant rats by intraperitoneal injection of chrysotile or crocidolite. Only Mut males injected with chrysotile revealed a promotional effect on mesothelial carcinogenesis in comparison with wild‐type and/or females, with all the MMs Brca1 haploinsufficient. Array‐based comparative genomic hybridization of MMs disclosed a greater extent of chromosomal deletions in Brca1 mutants, including Cdkn2a/2b accompanied by Tfr2 amplification, in comparison with wild‐type tumors. Mutant MMs indicated iron metabolism dysregulation, such as an increase in catalytic Fe(II) and Ki67‐index as well as a decrease in Fe(III) and ferritin expression. Simultaneously, mutant MMs revealed ferroptosis resistance by upregulation of Slc7A11 and Gpx4. At an early carcinogenic stage of 4 weeks, induced Brca1 expression in mesothelial cells was significantly suppressed in chrysotile/Mut in comparison with crocidolite/Mut, whereas significant preference to iron with a decrease in Fe(III) has been already established. In conclusion, chrysotile exposure can be a higher risk for MM in BRCA1 mutant males, considering the rat results.

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BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance

Cited by 15 publications

References 71 publications

Environmental impact on carcinogenesis under BRCA1 haploinsufficiency

Environmental impact on carcinogenesis under BRCA1 haploinsufficiency

Iron as spirit of life to share under monopoly

BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile‐induced mesothelioma via ferroptosis resistance

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