Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis

Song, Zhiyu; Jia, Gang; Ma, Peizhi; Cang, Shundong

doi:10.1016/j.lfs.2021.119399

Cited by 179 publications

(119 citation statements)

References 44 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…To study the resistance of ferroptosis, prior studies have mainly focused on the effects of intracellular antioxidant systems; however, extracellular signaling is less concerned. Although a few studies have demonstrated that exosome exerts roles to suppress ferroptosis in miRNAs-or proteins-dependent manners [42,43]. To the best of our knowledge, we proposed for the rst time that exosome and circRNA are also capable of desensitizing LUAD cells to ferroptosis via a FABP3-dependent reduction of global-AA and prevention of AA incorporation into the plasma membrane.…”

Section: Discussionmentioning

confidence: 93%

The Essential Roles of Exosome and CircRNA_101093 to Desensitize Lung Adenocarcinoma to Ferroptosis

Zhang¹,

Xu²,

Ma³

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundResistance to ferroptosis, a regulated cell death caused by iron-dependent excessive accumulation of lipid peroxides has recently been linked to lung adenocarcinoma (LUAD), the most prevalent lung cancer subtype. Despite intracellular antioxidant system is required for protection against ferroptosis, whether and how extracellular system desensitizes LUAD cells to ferroptosis is incompletely known. MethodsImmunohistochemistry (IHC) and immunoblotting (IB) were used to analyze protein expression, and quantitative RT-PCR (qPCR) was used to analyze mRNA level. Cell viability, cell death and the lipid reactive oxygen species (ROS) generation were measured to evaluate the responses to ferroptosis induction. Metabolites were measured using appropriate kits. Exosomes were observed using transmission electron microscope (TEM). The localization of arachidonic acid (AA) was detected using click chemistry labeling followed by confocal microscope observation. Interaction between RNA and protein were detected using RNA-pulldown, RNA immunoprecipitation (RIP) and photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Proteomic analysis was used to investigate circRNA_101093 (cir93) regulated protein and metabolomic analysis was used to analyze metabolites that changed among LUAD tissues expressing low and high Fatty acid-binding protein 3 (FABP3) levels. Cell-derived xenograft (CDX), patient-derived xenograft (PDX) and cell-implanted intrapulmonary LUAD mouse models and plasma/tissue specimens from LUAD patients were used to validate the mechanism that exosome and cir93 desensitized ferroptosis in LUAD. ResultsHere, the roles of exosome and circular RNA (circRNA) to desensitize LUAD cells to ferroptosis were investigated. Plasma exosome from LUAD patients exclusively reduced lipid peroxidation and desensitized ferroptosis. This might because exosomal-cir93 sustained an elevation of intracellular-cir93 in LUAD to modulate AA, a poly-unsaturated fatty acid that is critical for ferroptosis-associated over peroxidation in the plasma membrane. Mechanistically, cir93 interacted and lifted FABP3, which transported and facilitated AA reaction with taurine. Thus, global-AA was reduced while N-Arachidonoyl taurine (NAT), the product of AA and taurine, was induced. Notably, a role of NAT to suppress AA incorporation into plasma membrane was also revealed. In pre-clinical in vivo models, reducing exosome exhibited an improvement of ferroptosis-based treatment. ConclusionExosome and cir93 are essential for desensitizing LUAD cells to ferroptosis, and blocking exosome will be helpful for future LUAD treatment.

show abstract

Section: Discussionmentioning

confidence: 93%

The Essential Roles of Exosome and CircRNA_101093 to Desensitize Lung Adenocarcinoma to Ferroptosis

Zhang¹,

Xu²,

Ma³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…It has been reported that the interaction between miRNAs and anticancer drugs has diverse effects on oncogenesis. Some miRNAs (e.g., miR-522, miR-4443) are able to enhance resistance to cisplatin by inhibiting ferroptosis Song et al, 2021), while others (e.g., miR-4715-3p, miR-324-3p) sensitize cancer cells to cisplatin via induction of ferroptosis (Gomaa et al, 2019;Deng et al, 2021). In addition, the bioactivity of circRNAs has been implicated in the progression of ferroptosis and oncogenic regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, previous reports have revealed that miRNAs may influence the effect of ferroptosis inducers. Exosomal miR-4443 has been reported to inhibit cisplatin-induced ferroptosis and promote cisplatin resistance in NSCLC (Song et al, 2021). In lung adenocarcinoma cell A549, Deng et al (2021) found that miR-324-3p can enhance cisplatin-induced ferroptosis by targeting GPX4 directly.…”

Section: Non-coding Rnas a Prospective Point Of Oncogene Encodingmentioning

confidence: 98%

Ferroptosis Holds Novel Promise in Treatment of Cancer Mediated by Non-coding RNAs

Yuan

Gao

Wang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Ferroptosis is a newly identified form of regulated cell death that is associated with iron metabolism and oxidative stress. As a physiological mechanism, ferroptosis selectively removes cancer cells by regulating the expression of vital chemical molecules. Current findings on regulation of ferroptosis have largely focused on the function of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), in mediating ferroptotic cell death, while the sponging effect of circular RNAs (circRNAs) has not been widely studied. In this review, we discuss the molecular regulation of ferroptosis and highlight the value of circRNAs in controlling ferroptosis and carcinogenesis. Herein, we deliberate future role of this emerging form of regulated cell death in cancer therapeutics and predict the progression and prognosis of oncogenesis in future clinical therapy.

show abstract

“…Nonetheless, METTL3 may also have antitumor functions by enhancing chemotherapy sensitivity. In non-small cell lung carcinoma (NSCLC), METTL3 promotes the expression of FSP1, which enhances FSP1-mediated ferroptosis induced by cisplatin treatment [ 94 ]. In addition to METTL3, WTAP has also been associated with cisplatin resistance.…”

Section: M6a Methyltransferases In Chemotherapeutic Resistancementioning

confidence: 99%

“…When targeting METTL3 in NSCLC, miRNAs can be tumor suppressor genes, as we illustrate above, or oncogenes due to the context-dependent roles of METTL3 in cancer progression. It has been reported that miR-33a is capable of reducing cell proliferation [ 142 ], while exosomal miR-4443 promotes cisplatin resistance in NSCLC [ 94 ]. Sun et al found that, in addition to targeting METTL3, miR-103-3p can inhibit METTL14 expression and impair osteoblastic bone formation, which might result in osteoporosis [ 143 ].…”

Section: Targeting M6a Methyltransferase By Ncrnamentioning

confidence: 99%

N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

et al. 2021

View full text Add to dashboard Cite

N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.

show abstract

Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis

Cited by 179 publications

References 44 publications

The Essential Roles of Exosome and CircRNA_101093 to Desensitize Lung Adenocarcinoma to Ferroptosis

The Essential Roles of Exosome and CircRNA_101093 to Desensitize Lung Adenocarcinoma to Ferroptosis

Ferroptosis Holds Novel Promise in Treatment of Cancer Mediated by Non-coding RNAs

N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

Contact Info

Product

Resources

About