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Article

A Cystine-Cysteine Intercellular Shuttle Prevents Ferroptosis in xCTKO Pancreatic Ductal Adenocarcinoma Cells

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Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco, Monaco
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Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada
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Genome British Columbia Proteomics Centre, University of Victoria, Victoria, BC V8Z 7X8, Canada
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Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
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Department of Marine Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco, Monaco
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CNRS, INSERM, Centre A. Lacassagne, Institute for Research on Cancer & Aging (IRCAN), University Côte d’Azur, 06107 Nice, France
*
Authors to whom correspondence should be addressed.
Academic Editors: Deepak Nagrath and David Wong
Cancers 2021, 13(6), 1434; https://doi.org/10.3390/cancers13061434
Received: 25 January 2021 / Revised: 23 February 2021 / Accepted: 18 March 2021 / Published: 21 March 2021
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
The xCT transporter of oxidized form of cysteine has been recognized as fundamental for cellular amino acid and redox homeostasis. Increasing number of data suggests that xCT inhibition-induced ferroptosis has great potential for development of novel anti-cancer therapeutics for pancreatic cancer patients. The aim of this study was to investigate potential resistance mechanisms that cancer cells with genetically disrupted xCT (xCTKO) may exploit in order to develop resistance to ferroptosis. Our data clearly showed that shuttle of reduced cysteine between cancer xCTKO and neighboring cells provide protection of the former. Importantly, this shuttle seems to be fueled by the import and reduction of oxidized cysteine by xCT-proficient feeder layer. In summary, two important findings are: (1) supply of the reduced cysteine has to be taken in consideration when xCT-based ferroptosis inducers are used, and (2) systemic inhibition of xCT could be potential approach in overcoming this resistant mechanism.
In our previous study, we showed that a cystine transporter (xCT) plays a pivotal role in ferroptosis of pancreatic ductal adenocarcinoma (PDAC) cells in vitro. However, in vivo xCTKO cells grew normally indicating that a mechanism exists to drastically suppress the ferroptotic phenotype. We hypothesized that plasma and neighboring cells within the tumor mass provide a source of cysteine to confer full ferroptosis resistance to xCTKO PDAC cells. To evaluate this hypothesis, we (co-) cultured xCTKO PDAC cells with different xCT-proficient cells or with their conditioned media. Our data unequivocally showed that the presence of a cysteine/cystine shuttle between neighboring cells is the mechanism that provides redox and nutrient balance, and thus ferroptotic resistance in xCTKO cells. Interestingly, although a glutathione shuttle between cells represents a good alternative hypothesis as a “rescue-mechanism”, our data clearly demonstrated that the xCTKO phenotype is suppressed even with conditioned media from cells lacking the glutathione biosynthesis enzyme. Furthermore, we demonstrated that prevention of lipid hydroperoxide accumulation in vivo is mediated by import of cysteine into xCTKO cells via several genetically and pharmacologically identified transporters (ASCT1, ASCT2, LAT1, SNATs). Collectively, these data highlight the importance of the tumor environment in the ferroptosis sensitivity of cancer cells. View Full-Text
Keywords: cysteine-cystine shuttle; ferroptosis; resistance; tumor environment; cysteine transporters cysteine-cystine shuttle; ferroptosis; resistance; tumor environment; cysteine transporters
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MDPI and ACS Style

Meira, W.; Daher, B.; Parks, S.K.; Cormerais, Y.; Durivault, J.; Tambutte, E.; Pouyssegur, J.; Vučetić, M. A Cystine-Cysteine Intercellular Shuttle Prevents Ferroptosis in xCTKO Pancreatic Ductal Adenocarcinoma Cells. Cancers 2021, 13, 1434. https://doi.org/10.3390/cancers13061434

AMA Style

Meira W, Daher B, Parks SK, Cormerais Y, Durivault J, Tambutte E, Pouyssegur J, Vučetić M. A Cystine-Cysteine Intercellular Shuttle Prevents Ferroptosis in xCTKO Pancreatic Ductal Adenocarcinoma Cells. Cancers. 2021; 13(6):1434. https://doi.org/10.3390/cancers13061434

Chicago/Turabian Style

Meira, Willian, Boutaina Daher, Scott K. Parks, Yann Cormerais, Jerome Durivault, Eric Tambutte, Jacques Pouyssegur, and Milica Vučetić. 2021. "A Cystine-Cysteine Intercellular Shuttle Prevents Ferroptosis in xCTKO Pancreatic Ductal Adenocarcinoma Cells" Cancers 13, no. 6: 1434. https://doi.org/10.3390/cancers13061434

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