Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer
Nazia Chaudhary, Bhagya Shree Choudhary, Sanket Shah, Nileema Khapare, Nehanjali Dwivedi, Anagha Gaikwad, Neha Joshi, Jinsy Raichanna, Srikanta Basu, Murari Gurjar, Smitha P.K., Avanish Saklani, Poonam Gera, Mukta Ramadwar, Prachi Patil, Rahul Thorat, Vikram Gota, Sujan Dhar, Sanjay Gupta, Manjula Das, Sorab N. Dalal
Abstract
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.