Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer
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‐f...
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| Veröffentlicht in: | International journal of cancer 2021-10, Vol.149 (7), p.1495-1511 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1002/ijc.33711 |
| format | Article |
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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.</description><identifier>ISSN: 0020-7136</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.33711</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>5-Fluorouracil ; Animal models ; Cancer ; Chemotherapy ; chemo‐resistance ; Colon cancer ; Colorectal cancer ; Colorectal carcinoma ; Ets-1 protein ; Ferroptosis ; Glutathione ; Homeostasis ; Iron ; Lipocalin ; Lipocalin 2 ; Medical research ; Monoclonal antibodies ; Therapeutic targets ; Tumor cell lines ; Xenografts</subject><ispartof>International journal of cancer, 2021-10, Vol.149 (7), p.1495-1511</ispartof><rights>2021 UICC.</rights><rights>2021 UICC</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3651-130203ee135ffa56a2d6bc41c80971a66c4e99102a84cf4b64a4c1efd3be26e73</citedby><cites>FETCH-LOGICAL-c3651-130203ee135ffa56a2d6bc41c80971a66c4e99102a84cf4b64a4c1efd3be26e73</cites><orcidid>0000-0001-6883-7550</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fijc.33711$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fijc.33711$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids></links><search><creatorcontrib>Chaudhary, Nazia</creatorcontrib><creatorcontrib>Choudhary, Bhagya Shree</creatorcontrib><creatorcontrib>Shah, Sanket Girish</creatorcontrib><creatorcontrib>Khapare, Nileema</creatorcontrib><creatorcontrib>Dwivedi, Nehanjali</creatorcontrib><creatorcontrib>Gaikwad, Anagha</creatorcontrib><creatorcontrib>Joshi, Neha</creatorcontrib><creatorcontrib>Raichanna, Jinsy</creatorcontrib><creatorcontrib>Basu, Srikanta</creatorcontrib><creatorcontrib>Gurjar, Murari</creatorcontrib><creatorcontrib>P.K., Smitha</creatorcontrib><creatorcontrib>Saklani, Avanish</creatorcontrib><creatorcontrib>Gera, Poonam</creatorcontrib><creatorcontrib>Ramadwar, Mukta</creatorcontrib><creatorcontrib>Patil, Prachi</creatorcontrib><creatorcontrib>Thorat, Rahul</creatorcontrib><creatorcontrib>Gota, Vikram</creatorcontrib><creatorcontrib>Dhar, Sujan K.</creatorcontrib><creatorcontrib>Gupta, Sanjay</creatorcontrib><creatorcontrib>Das, Manjula</creatorcontrib><creatorcontrib>Dalal, Sorab N.</creatorcontrib><title>Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer</title><title>International journal of cancer</title><description>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.</description><subject>5-Fluorouracil</subject><subject>Animal models</subject><subject>Cancer</subject><subject>Chemotherapy</subject><subject>chemo‐resistance</subject><subject>Colon cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Ets-1 protein</subject><subject>Ferroptosis</subject><subject>Glutathione</subject><subject>Homeostasis</subject><subject>Iron</subject><subject>Lipocalin</subject><subject>Lipocalin 2</subject><subject>Medical research</subject><subject>Monoclonal antibodies</subject><subject>Therapeutic targets</subject><subject>Tumor cell lines</subject><subject>Xenografts</subject><issn>0020-7136</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp1kU9PwzAMxSMEEmNw4BtE4gKHbnGTtOsRTfwZmsQFzlWauVumtilJq9FvT0bhgsTJst_P1rMeIdfAZsBYPDd7PeM8BTghE2BZGrEY5CmZBI1FKfDknFx4v2cMQDIxIYe1aa1WlWloTPGzdei9sQ1tna1th552fW3dsd3-SqrZ0G6HTrUDDTPjO9VopMVATbMzhelMs6UlOmfbzgY5jKm2lXWoO1VRfaTdJTkrVeXx6qdOyfvjw9vyOVq_Pq2W9-tI80RCBDz45ojAZVkqmah4kxRagF6E30AliRaYZcBitRC6FEUilNCA5YYXGCeY8im5He-GDz569F1eG6-xqlSDtvd5LAUXQmYpD-jNH3Rve9cEd4GSWSazBWOBuhsp7az3Dsu8daZWbsiB5ccI8hBB_h1BYOcjezAVDv-D-eplOW58AeWVieI</recordid><startdate>20211001</startdate><enddate>20211001</enddate><creator>Chaudhary, Nazia</creator><creator>Choudhary, Bhagya Shree</creator><creator>Shah, Sanket Girish</creator><creator>Khapare, Nileema</creator><creator>Dwivedi, Nehanjali</creator><creator>Gaikwad, Anagha</creator><creator>Joshi, Neha</creator><creator>Raichanna, Jinsy</creator><creator>Basu, Srikanta</creator><creator>Gurjar, Murari</creator><creator>P.K., Smitha</creator><creator>Saklani, Avanish</creator><creator>Gera, Poonam</creator><creator>Ramadwar, Mukta</creator><creator>Patil, Prachi</creator><creator>Thorat, Rahul</creator><creator>Gota, Vikram</creator><creator>Dhar, Sujan K.</creator><creator>Gupta, Sanjay</creator><creator>Das, Manjula</creator><creator>Dalal, Sorab N.</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6883-7550</orcidid></search><sort><creationdate>20211001</creationdate><title>Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer</title><author>Chaudhary, Nazia ; 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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.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><doi>10.1002/ijc.33711</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-6883-7550</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 5-Fluorouracil Animal models Cancer Chemotherapy chemo‐resistance Colon cancer Colorectal cancer Colorectal carcinoma Ets-1 protein Ferroptosis Glutathione Homeostasis Iron Lipocalin Lipocalin 2 Medical research Monoclonal antibodies Therapeutic targets Tumor cell lines Xenografts |
| title | Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer |
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