MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
A collaborative study within the SPP 2306
Trumpp A, Westermann, F
Regulation of pro- and anti-ferroptotic players by oncogenic MYCN in MYCN-amplified neuroblastoma cells that may trigger ferroptosis when both cysteine and GSH availability is limited. Therapeutic intervention points are indicated in green.
(Figure adopted from Alborzinia H et al., 2022
Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.
Alborzinia H, Flórez AF, Kreth S, Brückner LM, Yildiz U, Gartlgruber M, Odoni DI, Poschet G, Garbowicz K, Shao C, Klein C, Meier J, Zeisberger P, Nadler-Holly M, Ziehm M, Paul F, Burhenne J, Bell E, Shaikhkarami M, Würth R, Stainczyk SA, Wecht EM, Kreth J, Büttner M, Ishaque N, Schlesner M, Nicke B, Stresemann C, Llamazares-Prada M, Reiling JH, Fischer M, Amit I, Selbach M, Herrmann C, Wölfl S, Henrich KO, Höfer T, Trumpp A, Westermann F.
Nat Cancer. 2022 Apr;3(4):471-485. doi: 10.1038/s43018-022-00355-4. Epub 2022 Apr 28. PMID: 35484422 Free PMC article.