Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 149, Issue 7, Pages 1495-1511Publisher
WILEY
DOI: 10.1002/ijc.33711
Keywords
chemo-resistance; colorectal cancer; ferroptosis; Lipocalin 2
Categories
Funding
- ACTREC donation fund [4338]
- Department of Biotechnology, Government of India [BT/PR8351/MED/30/995/2013]
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Lipocalin 2 overexpression leads to resistance to 5-fluorouracil in colon cancer cells by inhibiting ferroptosis. Inhibiting Lipocalin 2 function with a monoclonal antibody reduces chemoresistance and tumor progression. Lipocalin 2 and xCT exhibit a positive correlation in human tumor samples.
Lipocalin 2 is a siderophore-binding protein that regulates iron homeostasis. Lipocalin 2 expression is elevated in multiple tumor types; however, the mechanisms that drive tumor progression upon Lipocalin 2 expression remain unclear. When Lipocalin 2 is over-expressed, it leads to resistance to 5-fluorouracil in colon cancer cell lines in vitro and in vivo by inhibiting ferroptosis. Lipocalin 2 inhibits ferroptosis by decreasing intracellular iron levels and stimulating the expression of glutathione peroxidase4 and a component of the cysteine glutamate antiporter, xCT. The increase in xCT levels is dependent on increased levels of ETS1 in Lipocalin 2 over-expressing cells. Inhibiting Lipocalin 2 function with a monoclonal antibody leads to a decrease in chemo-resistance and transformation in vitro, and a decrease in tumor progression and chemo-resistance in xenograft mouse models. Lipocalin 2 and xCT levels exhibit a positive correlation in human tumor samples suggesting that the pathway we have identified in cell lines is operative in human tumor samples. These results indicate that Lipocalin 2 is a potential therapeutic target and that the monoclonal antibody described in our study can serve as the basis for a potential therapeutic in patients who do not respond to chemotherapy.
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