LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma

被引：42

作者：

Alborzinia, Hamed ^{[1
,2
]}

Chen, Zhiyi ^{[3
]}

Yildiz, Umut ^{[1
,2
,4
]}

Freitas, Florencio Porto ^{[3
]}

Vogel, Felix C. E. ^{[5
]}

Varga, Julianna Patricia ^{[6
]}

Batani, Jasmin ^{[3
]}

Bartenhagen, Christoph ^{[7
,8
]}

Schmitz, Werner ^{[9
]}

Buechel, Gabriele ^{[10
]}

Michalke, Bernhard ^{[11
]}

Zheng, Jashuo ^{[12
]}

Meierjohann, Svenja ^{[13
]}

Girardi, Enrico ^{[14
,15
]}

Espinet, Elisa ^{[16
,17
]}

Florez, Andres F. ^{[18
]}

dos Santos, Ancely Ferreira ^{[3
]}

Aroua, Nesrine

Cheytan, Tasneem

Haenlin, Julie

Schlicker, Lisa

da Silva, Thamara N. Xavier ^{[5
]}

Przybylla, Adriana

Zeisberger, Petra

Superti-Furga, Giulio ^{[19
]}

Eilers, Martin

Conrad, Marcus ^{[12
]}

Fabiano, Marietta ^{[20
]}

Schweizer, Ulrich

Fischer, Matthias

Schulze, Almut

Trumpp, Andreas ^{[1
]}

Angeli, Jose Pedro Friedmann ^{[2
,3
]}

机构：

[1] HI STEM GmbH, Heidelberg Inst Stem Cell Technol & Expt Med, Heidelberg, Germany

[2] German Canc Res Ctr, Div Stem Cells & Canc, Heidelberg, Germany

[3] Univ Wurzburg, Ctr Integrat & Translat Bioimaging, Rudolf Virchow Zent RVZ, Wurzburg, Germany

[4] European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany

[5] German Canc Res Ctr, Div Tumor Metab & Microenvironm, Heidelberg, Germany

[6] European Mol Biol Org, Heidelberg, Germany

[7] Univ Cologne, Ctr Mol Med Cologne CMMC, Cologne, Germany

[8] Univ Cologne, Univ Childrens Hosp, Med Fac, Dept Expt Pediat Oncol, Cologne, Germany

[9] Univ Wurzburg, Theodor Boveri Inst, Dept Biochem & Mol Biol, Bioctr, Wurzburg, Germany

[10] Univ Hosp Wurzburg, Mildred Scheel Early Career Ctr, Wurzburg, Germany

[11] Helmholtz Ctr Munchen HMGU, Res Unit Analyt Biogeochem, Neuherberg, Germany

[12] Helmholtz Zentrum Munchen HMGU, Inst Metab & Cell Death, Neuherberg, Germany

[13] Univ Wurzburg, Dept Pathol, Wurzburg, Germany

[14] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[15] Solgate GmbH, Klosterneuburg, Austria

[16] Univ Barcelona UB, Sch Med, Dept Pathol & Expt Therapy, Anat Unit, Lhospitalet De Llobregat, Barcelona, Spain

[17] Inst Invest Biomed Bellvitge IDIBELL, Mol Mech & Expt Therapy Oncol Program Oncobell, Lhospitalet De Llobregat, Barcelona, Spain

[18] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA USA

[19] Med Univ Vienna, Ctr Physiol & Pharmacol, Vienna, Austria

[20] Rhein Friedrich Wilhelms Univ Bonn, Inst Biochem & Molekularbiol, Bonn, Germany

来源：

EMBO MOLECULAR MEDICINE | 2023年 / 15卷 / 08期

基金：

欧洲研究理事会;

关键词：

ferroptosis; neuroblastoma; selenocysteine; selenoprotein; synthetic lethality; GLUTATHIONE-PEROXIDASE; 4; SELENOPROTEIN-P; SELENIUM UPTAKE; FERROPTOSIS; GPX4; INACTIVATION; DEPENDENCY; ACTIVATION; PATHWAY;

D O I：

10.15252/emmm.202318014

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc(-). The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.

引用

页数：17

共 47 条

[1] MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis [J].

Alborzinia, Hamed ;

Florez, Andres F. ;

Kreth, Sina ;

Brueckner, Lena M. ;

Yildiz, Umut ;

Gartlgruber, Moritz ;

Odoni, Dorett, I ;

Poschet, Gernot ;

Garbowicz, Karolina ;

Shao, Chunxuan ;

Klein, Corinna ;

Meier, Jasmin ;

Zeisberger, Petra ;

Nadler-Holly, Michal ;

Ziehm, Matthias ;

Paul, Franziska ;

Burhenne, Juergen ;

Bell, Emma ;

Shaikhkarami, Marjan ;

Wuerth, Roberto ;

Stainczyk, Sabine A. ;

Wecht, Elisa M. ;

Kreth, Jochen ;

Buettner, Michael ;

Ishaque, Naveed ;

Schlesner, Matthias ;

Nicke, Barbara ;

Stresemann, Carlo ;

Llamazares-Prada, Maria ;

Reiling, Jan H. ;

Fischer, Matthias ;

Amit, Ido ;

Selbach, Matthias ;

Herrmann, Carl ;

Woelfl, Stefan ;

Henrich, Kai-Oliver ;

Hoefer, Thomas ;

Trumpp, Andreas ;

Westermann, Frank .

NATURE CANCER, 2022, 3 (04) :471-+

[2] Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion [J].

Angeli, Jose Pedro Friedmann ;

Krysko, Dmitri, V ;

Conrad, Marcus .

NATURE REVIEWS CANCER, 2019, 19 (07) :405-414

[3] Selenium and GPX4, a vital symbiosis [J].

Angeli, Jose Pedro Friedmann ;

Conrad, Marcus .

FREE RADICAL BIOLOGY AND MEDICINE, 2018, 127 :153-159

[4] Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice [J].

Angeli, Jose Pedro Friedmann ;

Schneider, Manuela ;

Proneth, Bettina ;

Tyurina, Yulia Y. ;

Tyurin, Vladimir A. ;

Hammond, Victoria J. ;

Herbach, Nadja ;

Aichler, Michaela ;

Walch, Axel ;

Eggenhofer, Elke ;

Basavarajappa, Devaraj ;

Radmark, Olof ;

Kobayashi, Sho ;

Seibt, Tobias ;

Beck, Heike ;

Neff, Frauke ;

Esposito, Irene ;

Wanke, Ruediger ;

Foerster, Heidi ;

Yefremova, Olena ;

Heinrichmeyer, Marc ;

Bornkamm, Georg W. ;

Geissler, Edward K. ;

Thomas, Stephen B. ;

Stockwell, Brent R. ;

O'Donnell, Valerie B. ;

Kagan, Valerian E. ;

Schick, Joel A. ;

Conrad, Marcus .

NATURE CELL BIOLOGY, 2014, 16 (12) :1180-U120

[5] An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules [J].

Basu, Amrita ;

Bodycombe, Nicole E. ;

Cheah, Jaime H. ;

Price, Edmund V. ;

Liu, Ke ;

Schaefer, Giannina I. ;

Ebright, Richard Y. ;

Stewart, Michelle L. ;

Ito, Daisuke ;

Wang, Stephanie ;

Bracha, Abigail L. ;

Liefeld, Ted ;

Wawer, Mathias ;

Gilbert, Joshua C. ;

Wilson, Andrew J. ;

Stransky, Nicolas ;

Kryukov, Gregory V. ;

Dancik, Vlado ;

Barretina, Jordi ;

Garraway, Levi A. ;

Hon, C. Suk-Yee ;

Munoz, Benito ;

Bittker, Joshua A. ;

Stockwell, Brent R. ;

Khabele, Dineo ;

Stern, Andrew M. ;

Clemons, Paul A. ;

Shamji, Alykhan F. ;

Schreiber, Stuart L. .

CELL, 2013, 154 (05) :1151-1161

[6] The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis [J].

Bersuker, Kirill ;

Hendricks, Joseph M. ;

Li, Zhipeng ;

Magtanong, Leslie ;

Ford, Breanna ;

Tang, Peter H. ;

Roberts, Melissa A. ;

Tong, Bingqi ;

Maimone, Thomas J. ;

Zoncu, Roberto ;

Bassik, Michael C. ;

Nomura, Daniel K. ;

Dixon, Scott J. ;

Olzmann, James A. .

NATURE, 2019, 575 (7784) :688-+

[7] Expression of Inactive Glutathione Peroxidase 4 Leads to Embryonic Lethality, and Inactivation of the Alox15 Gene Does Not Rescue Such Knock-In Mice [J].

Bruetsch, Simone Hanna ;

Wang, Chi Chiu ;

Li, Lu ;

Stender, Hannelore ;

Neziroglu, Nilguen ;

Richter, Constanze ;

Kuhn, Hartmut ;

Borchert, Astrid .

ANTIOXIDANTS & REDOX SIGNALING, 2015, 22 (04) :281-293

[8] Deletion of selenoprotein P upregulates urinary selenium excretion and depresses whole-body selenium content [J].

Burk, Raymond F. ;

Hill, Kristina E. ;

Motley, Amy K. ;

Austin, Lori M. ;

Norsworthy, Brooke K. .

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 2006, 1760 (12) :1789-1793

[9] Regulation of Selenium Metabolism and Transport [J].

Burk, Raymond F. ;

Hill, Kristina E. .

ANNUAL REVIEW OF NUTRITION, VOL 35, 2015, 35 :109-134

[10] Selenium detoxification is required for cancer-cell survival [J].

Carlisle, Anne E. ;

Lee, Namgyu ;

Matthew-Onabanjo, Asia N. ;

Spears, Meghan E. ;

Park, Sung Jin ;

Youkana, Daniel ;

Doshi, Mihir B. ;

Peppers, Austin ;

Li, Rui ;

Joseph, Alexander B. ;

Smith, Miles ;

Simin, Karl ;

Zhu, Lihua Julie ;

Greer, Paul L. ;

Shaw, Leslie M. ;

Kim, Dohoon .

NATURE METABOLISM, 2020, 2 (07) :603-+

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