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Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer
Author(s) -
Chaudhary Nazia,
Choudhary Bhagya Shree,
Shah Sanket Girish,
Khapare Nileema,
Dwivedi Nehanjali,
Gaikwad Anagha,
Joshi Neha,
Raichanna Jinsy,
Basu Srikanta,
Gurjar Murari,
P.K. Smitha,
Saklani Avanish,
Gera Poonam,
Ramadwar Mukta,
Patil Prachi,
Thorat Rahul,
Gota Vikram,
Dhar Sujan K.,
Gupta Sanjay,
Das Manjula,
Dalal Sorab N.
Publication year - 2021
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33711
Subject(s) - lipocalin , cancer research , tumor progression , cell culture , in vivo , cancer , in vitro , biology , intracellular , monoclonal antibody , antibody , immunology , microbiology and biotechnology , biochemistry , genetics
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.