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The Role of Lipocalin 2 (LCN2) in Regulating Ferroptosis and Therapy Resistance
CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2022; 43(S 01): S1-S19
DOI: DOI: 10.1055/s-0042-1755493
Correspondence to: sdalal@actrec.gov.in
Background: Increased expression of LCN2 leads to chemoresistance and inhibiting LCN2 function results in chemosensitivity, due to LCN2-mediated inhibition of iron-dependent programmed cell death process called ferroptosis and induction of autophagy. We aim to assess how LCN2 stimulates ETS1 expression to inhibit ferroptosis and how LCN2 promotes autophagy leading to chemoresistance.
Materials and Methods: All the protocols have been described previously in Chaudhary et al. shRNA was cloned into pLKO.1-TRC cloning vector (a gift from David Root) to generate stable LCN2 knockdown in DLD1 cells to confirm the observation obtained with the LCN2 antibody (3D12B2).
Results: LCN2 overexpressing cells showed increased levels of ETS1, xCT, and GPX4, while LCN2 knockdown cells showed decreased levels, confirming the results obtained by treatment with LCN2 antibody, and consistent with the observation that LCN2 promotes resistance to 5-FU by inhibiting ferroptosis. Further, LCN2 overexpressing cells showed increased LC3II levels and increased LC3 foci, suggesting LCN2 promotes autophagy in response to therapy. Also, activated EGFR expression is decreased in LCN2 knockdown cells suggesting that the increase in ETS1 levels observed upon LCN2 expression is probably due to increased activity of EGFR.
Conclusion: LCN2 inhibits ferroptosis by increasing ETS1 expression and promotes autophagy. By inducing autophagy, it probably increases the recycling of EGFR, such that activation of EGFR signaling increases expression of ETS1 which inhibits ferroptosis to promote chemoresistance.
Publication History
Article published online:
22 August 2022
© 2022. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
Correspondence to: sdalal@actrec.gov.in
Background: Increased expression of LCN2 leads to chemoresistance and inhibiting LCN2 function results in chemosensitivity, due to LCN2-mediated inhibition of iron-dependent programmed cell death process called ferroptosis and induction of autophagy. We aim to assess how LCN2 stimulates ETS1 expression to inhibit ferroptosis and how LCN2 promotes autophagy leading to chemoresistance.
Materials and Methods: All the protocols have been described previously in Chaudhary et al. shRNA was cloned into pLKO.1-TRC cloning vector (a gift from David Root) to generate stable LCN2 knockdown in DLD1 cells to confirm the observation obtained with the LCN2 antibody (3D12B2).
Results: LCN2 overexpressing cells showed increased levels of ETS1, xCT, and GPX4, while LCN2 knockdown cells showed decreased levels, confirming the results obtained by treatment with LCN2 antibody, and consistent with the observation that LCN2 promotes resistance to 5-FU by inhibiting ferroptosis. Further, LCN2 overexpressing cells showed increased LC3II levels and increased LC3 foci, suggesting LCN2 promotes autophagy in response to therapy. Also, activated EGFR expression is decreased in LCN2 knockdown cells suggesting that the increase in ETS1 levels observed upon LCN2 expression is probably due to increased activity of EGFR.
Conclusion: LCN2 inhibits ferroptosis by increasing ETS1 expression and promotes autophagy. By inducing autophagy, it probably increases the recycling of EGFR, such that activation of EGFR signaling increases expression of ETS1 which inhibits ferroptosis to promote chemoresistance.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
22 August 2022
© 2022. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India