MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

Abstract

MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(−) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.

Syrian hamsters as a model of lung injury with SARS-CoV-2 infection: Pathologic, physiologic, and detailed molecular profiling

“…5C, D). To further support these findings, we stained hamster lung tissue sections and observe positive TUNEL staining, consistent with apoptosis, with peak at 7 dpi and increased TFRC (Transferrin Receptor Protein 1), a specific marker of ferroptosis [ 54 , 55 ], staining by IHC, again most evident at 7 dpi ( Fig. 6 D).…”

Identification and validation of an individualized prognostic signature of lung squamous cell carcinoma based on ferroptosis‐related genes

“… 39 Upregulation of TRFC promoted ferroptosis by increasing the intracellular iron load. 40 RRM2, JUN, and TP63 were found to increase cellular resistance against ferroptosis by regulating the synthesis, utilization, and regeneration of glutathione. 41 , 42 , 43 A previous study indicated that overexpression of ENPP2 could inhibit erastin‐induced ferroptosis.…”

CircPTCH1 Promotes Migration in Lung Cancer by Regulating MYCN Expression Through miR-34c-5p

“…The N-myc protein encoded by MYCN gene is an important transcription factor, which can regulate the expression of a variety of target genes and thus participate in a variety of cell biological functions and signaling pathways. 33 , 34 Studies have shown that MYCN can directly target cell cycle-related genes, reduce G1 phase arrest, promote cell into S phase and promote cell proliferation. 33 , 35 The abnormal expression of MYCN was found in neurogenic tumors, including neuroblastoma, neuroendocrine prostate cancer and small cell lung cancer.…”