Targeting ErbB3 and Cellular NADPH/NADP Abundance Sensitizes Cutaneous Melanomas to Ferroptosis Inducers

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2022 Apr 14

PMID 35420772

Authors

Julia I. Leu

Maureen E Murphy

Donna L George

Affiliations

Soon will be listed here.

Abstract

Melanoma is a serious health challenge. Ferroptosis is a regulated form of oxidative cell death that shows varied efficacy in melanoma. We aimed to better understand the molecular basis for this differential ferroptosis sensitivity. We find that elevated expression of ErbB3 (V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homologue 3) associates with ferroptosis resistance and that ErbB3 knockdown sensitizes to ferroptosis inducers. ErbB3 depletion also promotes a marked reduction in the cellular ratio of GSH/GSSG (reduced/oxidized glutathione) and that of NADPH/NADP (reduced/oxidized nicotinamide adenine dinucleotide phosphate), together with an increase in the abundance of the lipid peroxidation product malondialdehyde (MDA). We identify several small molecule inhibitors targeting ErbB3 signaling pathways that also reduce the NADPH/NADP and GSH/GSSG ratios, concomitantly sensitizing the melanomas to ferroptosis activators. These findings point to a previously unrecognized role of ErbB3 in ferroptosis sensitivity and provide new insight into pathways that regulate this cell death process.

Citing Articles

Revealing the role of RAB27 in HER receptor family expression and signaling in melanoma cells.

Horodecka K, Czernek L, Peczek L, Klink M Cell Commun Signal. 2025; 23(1):118.

PMID: 40038749 PMC: 11877929. DOI: 10.1186/s12964-025-02064-8.

Ferroptosis: a promising target for fumarate hydratase-deficient tumor therapeutics literature review.

Cheng P, Xia R, Wang X Transl Cancer Res. 2024; 13(6):3126-3141.

PMID: 38988939 PMC: 11231789. DOI: 10.21037/tcr-24-21.

The application of approaches in detecting ferroptosis.

Chen Z, Lin H, Wang X, Li G, Liu N, Zhang M Heliyon. 2024; 10(1):e23507.

PMID: 38187349 PMC: 10767388. DOI: 10.1016/j.heliyon.2023.e23507.

Ferroptosis as a promising therapeutic strategy for melanoma.

Ta N, Jiang X, Zhang Y, Wang H Front Pharmacol. 2023; 14:1252567.

PMID: 37795022 PMC: 10546212. DOI: 10.3389/fphar.2023.1252567.

Harnessing the Potential of Non-Apoptotic Cell Death Processes in the Treatment of Drug-Resistant Melanoma.

Dong L, Vargas C, Tian X, Chu X, Yin C, Wong A Int J Mol Sci. 2023; 24(12).

PMID: 37373523 PMC: 10299440. DOI: 10.3390/ijms241210376.

References

Parris J, Barnoud T, Leu J, Leung J, Ma W, Kirven N . HSP70 inhibition blocks adaptive resistance and synergizes with MEK inhibition for the treatment of NRAS-mutant melanoma. Cancer Res Commun. 2022; 1(1):17-29. PMC: 8849551. DOI: 10.1158/2767-9764.crc-21-0033. View

Armenta D, Dixon S . Investigating Nonapoptotic Cell Death Using Chemical Biology Approaches. Cell Chem Biol. 2020; 27(4):376-386. PMC: 7185180. DOI: 10.1016/j.chembiol.2020.03.005. View

Ong Q, Guo S, Zhang K, Cui B . U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor. ACS Chem Neurosci. 2014; 6(1):130-7. PMC: 4304487. DOI: 10.1021/cn500288n. View

Leu J, Pimkina J, Frank A, Murphy M, George D . A small molecule inhibitor of inducible heat shock protein 70. Mol Cell. 2009; 36(1):15-27. PMC: 2771108. DOI: 10.1016/j.molcel.2009.09.023. View

Leu J, Murphy M, George D . Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of . Proc Natl Acad Sci U S A. 2020; 117(43):26804-26811. PMC: 7604449. DOI: 10.1073/pnas.2009943117. View

Haikala H, Janne P . Thirty Years of HER3: From Basic Biology to Therapeutic Interventions. Clin Cancer Res. 2021; 27(13):3528-3539. PMC: 8254743. DOI: 10.1158/1078-0432.CCR-20-4465. View

Talty R, Bosenberg M . The role of ferroptosis in melanoma. Pigment Cell Melanoma Res. 2021; 35(1):18-25. DOI: 10.1111/pcmr.13009. View

Leu J, Murphy M, George D . Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53. Proc Natl Acad Sci U S A. 2019; 116(17):8390-8396. PMC: 6486733. DOI: 10.1073/pnas.1821277116. View

Black L, Longo J, Carroll S . Mechanisms of Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3) Action in Human Neoplasia. Am J Pathol. 2019; 189(10):1898-1912. PMC: 6892224. DOI: 10.1016/j.ajpath.2019.06.008. View

10.

Barnoud T, Leung J, Leu J, Basu S, Poli A, Parris J . A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors. Cancer Res. 2020; 80(23):5270-5281. PMC: 7718317. DOI: 10.1158/0008-5472.CAN-20-0397. View

11.

Conlon M, Poltorack C, Forcina G, Armenta D, Mallais M, Perez M . A compendium of kinetic modulatory profiles identifies ferroptosis regulators. Nat Chem Biol. 2021; 17(6):665-674. PMC: 8159879. DOI: 10.1038/s41589-021-00751-4. View

12.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

13.

Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V . AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011; 19(1):58-71. PMC: 3025058. DOI: 10.1016/j.ccr.2010.10.031. View

14.

Jiang X, Stockwell B, Conrad M . Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266-282. PMC: 8142022. DOI: 10.1038/s41580-020-00324-8. View

15.

Leu J, Zhang P, Murphy M, Marmorstein R, George D . Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket. ACS Chem Biol. 2014; 9(11):2508-16. PMC: 4241170. DOI: 10.1021/cb500236y. View

16.

Capparelli C, Rosenbaum S, Berman-Booty L, Salhi A, Gaborit N, Zhan T . ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas. Cancer Res. 2015; 75(17):3554-67. PMC: 4558382. DOI: 10.1158/0008-5472.CAN-14-2959. View

17.

Chen X, Kang R, Kroemer G, Tang D . Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021; 18(5):280-296. DOI: 10.1038/s41571-020-00462-0. View

18.

Shimada K, Hayano M, Pagano N, Stockwell B . Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity. Cell Chem Biol. 2016; 23(2):225-235. PMC: 4792701. DOI: 10.1016/j.chembiol.2015.11.016. View

19.

Emmons M, Smalley K . Ironing-Out the Details: New Strategies for Combining Ferroptosis Inhibitors with Immunotherapy in Melanoma. J Invest Dermatol. 2021; 142(1):18-20. DOI: 10.1016/j.jid.2021.06.014. View

20.

Yi J, Zhu J, Wu J, Thompson C, Jiang X . Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc Natl Acad Sci U S A. 2020; 117(49):31189-31197. PMC: 7733797. DOI: 10.1073/pnas.2017152117. View