Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer
Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) pl...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723002343 |
| _version_ | 1797741384326709248 |
|---|---|
| author | Krishan Kumar Saini Priyank Chaturvedi Abhipsa Sinha Manish Pratap Singh Muqtada Ali Khan Ayushi Verma Mushtaq Ahmad Nengroo Saumya Ranjan Satrusal Sanjeev Meena Akhilesh Singh Sameer Srivastava Jayanta Sarkar Dipak Datta |
| author_facet | Krishan Kumar Saini Priyank Chaturvedi Abhipsa Sinha Manish Pratap Singh Muqtada Ali Khan Ayushi Verma Mushtaq Ahmad Nengroo Saumya Ranjan Satrusal Sanjeev Meena Akhilesh Singh Sameer Srivastava Jayanta Sarkar Dipak Datta |
| author_sort | Krishan Kumar Saini |
| collection | DOAJ |
| description | Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition. |
| first_indexed | 2024-03-12T14:26:59Z |
| format | Article |
| id | doaj.art-17f9687ba0704e9487a9e183d5bf98cf |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-12T14:26:59Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-17f9687ba0704e9487a9e183d5bf98cf2023-08-18T04:31:07ZengElsevierRedox Biology2213-23172023-09-0165102833Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancerKrishan Kumar Saini0Priyank Chaturvedi1Abhipsa Sinha2Manish Pratap Singh3Muqtada Ali Khan4Ayushi Verma5Mushtaq Ahmad Nengroo6Saumya Ranjan Satrusal7Sanjeev Meena8Akhilesh Singh9Sameer Srivastava10Jayanta Sarkar11Dipak Datta12Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, IndiaDepartment of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, 211004, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, IndiaDivision of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India; Corresponding author. Division of Cancer Biology, CSIR-CDRI, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.http://www.sciencedirect.com/science/article/pii/S2213231723002343ER stressUPRPERKSLC7A11FerroptosisCancer |
| spellingShingle | Krishan Kumar Saini Priyank Chaturvedi Abhipsa Sinha Manish Pratap Singh Muqtada Ali Khan Ayushi Verma Mushtaq Ahmad Nengroo Saumya Ranjan Satrusal Sanjeev Meena Akhilesh Singh Sameer Srivastava Jayanta Sarkar Dipak Datta Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer Redox Biology ER stress UPR PERK SLC7A11 Ferroptosis Cancer |
| title | Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer |
| title_full | Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer |
| title_fullStr | Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer |
| title_full_unstemmed | Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer |
| title_short | Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer |
| title_sort | loss of perk function promotes ferroptosis by downregulating slc7a11 system xc⁻ in colorectal cancer |
| topic | ER stress UPR PERK SLC7A11 Ferroptosis Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723002343 |
| work_keys_str_mv | AT krishankumarsaini lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT priyankchaturvedi lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT abhipsasinha lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT manishpratapsingh lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT muqtadaalikhan lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT ayushiverma lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT mushtaqahmadnengroo lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT saumyaranjansatrusal lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT sanjeevmeena lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT akhileshsingh lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT sameersrivastava lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT jayantasarkar lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer AT dipakdatta lossofperkfunctionpromotesferroptosisbydownregulatingslc7a11systemxcincolorectalcancer |