Research status and future prospect of ferroptosis in pancreatic cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHOU Wei ,  WU Heshui

Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China;

Corresponding author：

WU Heshui, Email: heshuiwu@163.com

Keywords：

pancreatic cancer; programmed cell death; ferroptosis

DOI：

10.7507/1007-9424.202209012

Video：

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Objective To understand the molecular mechanism of ferroptosis and its research progress and future prospects in pancreatic cancer. Method The relevant literature on the molecular mechanism of ferroptosis and its basic and clinical application in the occurrence and development of pancreatic cancer was retrievaled and reviewed. Results Ferroptosis was a non-apoptotic form of cell death that depended on iron aggregation, and its molecular biological features included iron ion overload, reactive oxygen species accumulation, lipid peroxidation, and so on. Ferroptosis was closely related to cell metabolism, and the imbalance of ferroptosis caused by abnormal metabolism also existed during the tumorigenesis and progression of pancreatic cancer, which in turn triggered the abnormal proliferation of pancreatic cancer cells and leaded to their progression. By regulating the key molecular signaling pathways of ferroptosis, it was expected to find new drug targets and therapeutic pathways for pancreatic cancer treatment. The results of ferroptosis-related studies so far had shown the potential for future translational research in the field of pancreatic cancer treatment. Conclusions The mechanism of ferroptosis is of great value in pancreatic cancer research. At present, there are still many uncharted areas in the study of ferroptosis, and the molecular mechanisms involved are still poorly understood. In the future, as the study of ferroptosis continues, it is expected to provide new ideas for pancreatic cancer treatment and discover new targets for drug development.

Citation： ZHOU Wei, WU Heshui. Research status and future prospect of ferroptosis in pancreatic cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(3): 364-368. doi: 10.7507/1007-9424.202209012 Copy

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2.	Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
3.	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
4.	Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab, 2020, 32(6): 920-937.
5.	Jiang M, Qiao M, Zhao C, et al. Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers. Transl Lung Cancer Res, 2020, 9(4): 1569-1584.
6.	Tang D, Chen X, Kang R, et al. Ferroptosis: molecular mechanisms and health implications. Cell Res, 2021, 31(2): 107-125.
7.	Yang Y, Zhang ZJ, Wen Y, et al. Novel perspective in pancreatic cancer therapy: targeting ferroptosis pathway. World J Gastrointest Oncol, 2021, 13(11): 1668-1679.
8.	Chen X, Kang R, Kroemer G, et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol, 2021, 18(5): 280-296.
9.	Battaglia AM, Chirillo R, Aversa I, et al. Ferroptosis and cancer: mitochondria meet the “Iron Maiden” cell death. Cells, 2020, 9(6): 1505. doi: 10.3390/cells9061505.
10.	Yang J, Xu J, Zhang B, et al. Ferroptosis: at the crossroad of gemcitabine resistance and tumorigenesis in pancreatic cancer. Int J Mol Sci, 2021, 22(20): 10944. doi: 10.3390/ijms222010944.
11.	Liu J, Dai E, Kang R, et al. The dark side of ferroptosis in pancreatic cancer. Oncoimmunology, 2021, 10(1): 1868691. doi: 10.1080/2162402X.2020.1868691.
12.	Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology, 2016, 63(1): 173-184.
13.	Wang Y, Liu Y, Liu J, et al. NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochem Biophys Res Commun, 2020, 531(4): 581-587.
14.	Chakraborty S, Kaur S, Guha S, et al. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta, 2012, 1826(1): 129-169.
15.	Liu J, Kang R, Tang D. The art of war: ferroptosis and pancreatic cancer. Front Pharmacol, 2021, 12: 773909. doi: 10.3389/fphar.2021.773909.
16.	Song X, Liu J, Kuang F, et al. PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis. Cell Rep, 2021, 34(8): 108767. doi: 10.1016/j.celrep.2021.108767.
17.	Daher B, Parks SK, Durivault J, et al. Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival, and tumor formation via nutrient and oxidative stresses. Cancer Res, 2019, 79(15): 3877-3890.
18.	Liu M, Kong XY, Yao Y, et al. The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review. Ann Transl Med, 2022, 10(6): 368. doi: 10.21037/atm-21-6942.
19.	Wen Y, Chen H, Zhang L, et al. Glycyrrhetinic acid induces oxidative/nitrative stress and drives ferroptosis through activating NADPH oxidases and iNOS, and depriving glutathione in triple-negative breast cancer cells. Free Radical Biology and Medicine, 2021, 173: 41-51.
20.	Chen C, Chen W, Zhou X, et al. Hyperbaric oxygen protects HT22 cells and PC12 cells from damage caused by oxygen-glucose deprivation/reperfusion via the inhibition of Nrf2/System Xc^–/GPX4 axis-mediated ferroptosis. PLoS One, 2022, 17(11): e0276083. doi: 10.1371/journal.pone.0276083.
21.	Zhu G, Murshed A, Li H, et al. O-GlcN acylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer. Cell Death Discov, 2021, 7(1): 83. doi: 10.1038/s41420-021-00468-2.
22.	Liu Y, Song Z, Liu Y, et al. Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer. Acta Pharm Sin B, 2021, 11(6): 1513-1525.
23.	Alborzinia H, Flórez AF, Kreth S, et al. MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat Cancer, 2022, 3(4): 471-485.
24.	Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature, 2015, 520(7545): 57-62.
25.	Zhang X, Zheng Q, Yue X, et al. ZNF498 promotes hepatocellular carcinogenesis by suppressing p53-mediated apoptosis and ferroptosis via the attenuation of p53 Ser46 phosphorylation. J Exp Clin Cancer Res, 2022, 41(1): 79. doi: 10.1186/s13046-022-02288-3.
26.	Chu B, Kon N, Chen D, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol, 2019, 21(5): 579-591.
27.	Yu M, Wang W, Dang J, et al. Hydrogen sulfide protects retinal pigment epithelium cells against ferroptosis through the AMPK- and p62-dependent non-canonical NRF2-KEAP1 pathway. Exp Cell Res, 2023, 422(1): 113436. doi: 10.1016/j.yexcr.2022.113436.
28.	Liu Y, Huang P, Li Z, et al. Vitamin C sensitizes pancreatic cancer cells to Erastin-induced ferroptosis by activating the AMPK/Nrf2/HMOX1 pathway. Oxid Med Cell Longev, 2022, 2022: 5361241. doi: 10.1155/2022/5361241.
29.	Torphy RJ, Fujiwara Y, Schulick RD. Pancreatic cancer treatment: better, but a long way to go. Surg Today, 2020, 50(10): 1117-1125.
30.	Kim HJ, Lee HN, Jeong MS, et al. Oncogenic KRAS: signaling and drug resistance. Cancers, 2021, 13(22): 5599. doi: 10.3390/cancers13225599.
31.	Dai E, Han L, Liu J, et al. Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun, 2020, 11(1): 6339. doi: 10.1038/s41467-020-20154-8.
32.	Hu S, Sechi M, Singh PK, et al. A novel redox modulator induces a GPX4-mediated cell death that is dependent on iron and reactive oxygen species. J Med Chem, 2020, 63(17): 9838-9855.
33.	Song R, Li T, Ye J, et al. Acidity-activatable dynamic nanoparticles boosting ferroptotic cell death for immunotherapy of cancer. Adv Mater, 2021, 33(31): e2101155. doi: 10.1002/adma.202101155.
34.	Liu S, Zhao X, Shui S, et al. PDTAC: targeted photodegradation of GPX4 triggers ferroptosis and potent antitumor immunity. J Med Chem, 2022, 65(18): 12176-12187.
35.	Zhou A, Fang T, Chen K, et al. Biomimetic activator of sonodynamic ferroptosis amplifies inherent peroxidation for improving the treatment of breast cancer. Small, 2022, 18(12): e2106568. doi: 10.1002/smll.202106568.
36.	马里程, 农晓琳. 青蒿琥酯抗肿瘤作用机制研究进展. 中华肿瘤防治杂志, 2020, 27(11): 921-926.
37.	Ooko E, Saeed ME, Kadioglu O, et al. Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine, 2015, 22(11): 1045-1054.
38.	Song Z, Xiang X, Li J, et al. Ruscogenin induces ferroptosis in pancreatic cancer cells. Oncol Rep, 2020, 43(2): 516-524.
39.	Zhao J, He B, Seshadri VD, et al. Anticancer effect of ruscogenin in B(a)P-induced lung cancer in mice via modulation of proinflammatory cytokines and mitochondrial enzymes. Appl Biochem Biotechnol, 2022, 194(12): 5862-5877.
40.	Lv Y, Wu X, Chen J, et al. Ruscogenin attenuated tight junction injury and tumor migration in colorectal liver metastasis mice via regulating TRAP1. Transl Cancer Res, 2021, 10(3): 1470-1483.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
2. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
3. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
4. Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab, 2020, 32(6): 920-937.
5. Jiang M, Qiao M, Zhao C, et al. Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers. Transl Lung Cancer Res, 2020, 9(4): 1569-1584.
6. Tang D, Chen X, Kang R, et al. Ferroptosis: molecular mechanisms and health implications. Cell Res, 2021, 31(2): 107-125.
7. Yang Y, Zhang ZJ, Wen Y, et al. Novel perspective in pancreatic cancer therapy: targeting ferroptosis pathway. World J Gastrointest Oncol, 2021, 13(11): 1668-1679.
8. Chen X, Kang R, Kroemer G, et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol, 2021, 18(5): 280-296.
9. Battaglia AM, Chirillo R, Aversa I, et al. Ferroptosis and cancer: mitochondria meet the “Iron Maiden” cell death. Cells, 2020, 9(6): 1505. doi: 10.3390/cells9061505.
10. Yang J, Xu J, Zhang B, et al. Ferroptosis: at the crossroad of gemcitabine resistance and tumorigenesis in pancreatic cancer. Int J Mol Sci, 2021, 22(20): 10944. doi: 10.3390/ijms222010944.
11. Liu J, Dai E, Kang R, et al. The dark side of ferroptosis in pancreatic cancer. Oncoimmunology, 2021, 10(1): 1868691. doi: 10.1080/2162402X.2020.1868691.
12. Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology, 2016, 63(1): 173-184.
13. Wang Y, Liu Y, Liu J, et al. NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochem Biophys Res Commun, 2020, 531(4): 581-587.
14. Chakraborty S, Kaur S, Guha S, et al. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta, 2012, 1826(1): 129-169.
15. Liu J, Kang R, Tang D. The art of war: ferroptosis and pancreatic cancer. Front Pharmacol, 2021, 12: 773909. doi: 10.3389/fphar.2021.773909.
16. Song X, Liu J, Kuang F, et al. PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis. Cell Rep, 2021, 34(8): 108767. doi: 10.1016/j.celrep.2021.108767.
17. Daher B, Parks SK, Durivault J, et al. Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival, and tumor formation via nutrient and oxidative stresses. Cancer Res, 2019, 79(15): 3877-3890.
18. Liu M, Kong XY, Yao Y, et al. The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review. Ann Transl Med, 2022, 10(6): 368. doi: 10.21037/atm-21-6942.
19. Wen Y, Chen H, Zhang L, et al. Glycyrrhetinic acid induces oxidative/nitrative stress and drives ferroptosis through activating NADPH oxidases and iNOS, and depriving glutathione in triple-negative breast cancer cells. Free Radical Biology and Medicine, 2021, 173: 41-51.
20. Chen C, Chen W, Zhou X, et al. Hyperbaric oxygen protects HT22 cells and PC12 cells from damage caused by oxygen-glucose deprivation/reperfusion via the inhibition of Nrf2/System Xc^–/GPX4 axis-mediated ferroptosis. PLoS One, 2022, 17(11): e0276083. doi: 10.1371/journal.pone.0276083.
21. Zhu G, Murshed A, Li H, et al. O-GlcN acylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer. Cell Death Discov, 2021, 7(1): 83. doi: 10.1038/s41420-021-00468-2.
22. Liu Y, Song Z, Liu Y, et al. Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer. Acta Pharm Sin B, 2021, 11(6): 1513-1525.
23. Alborzinia H, Flórez AF, Kreth S, et al. MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat Cancer, 2022, 3(4): 471-485.
24. Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature, 2015, 520(7545): 57-62.
25. Zhang X, Zheng Q, Yue X, et al. ZNF498 promotes hepatocellular carcinogenesis by suppressing p53-mediated apoptosis and ferroptosis via the attenuation of p53 Ser46 phosphorylation. J Exp Clin Cancer Res, 2022, 41(1): 79. doi: 10.1186/s13046-022-02288-3.
26. Chu B, Kon N, Chen D, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol, 2019, 21(5): 579-591.
27. Yu M, Wang W, Dang J, et al. Hydrogen sulfide protects retinal pigment epithelium cells against ferroptosis through the AMPK- and p62-dependent non-canonical NRF2-KEAP1 pathway. Exp Cell Res, 2023, 422(1): 113436. doi: 10.1016/j.yexcr.2022.113436.
28. Liu Y, Huang P, Li Z, et al. Vitamin C sensitizes pancreatic cancer cells to Erastin-induced ferroptosis by activating the AMPK/Nrf2/HMOX1 pathway. Oxid Med Cell Longev, 2022, 2022: 5361241. doi: 10.1155/2022/5361241.
29. Torphy RJ, Fujiwara Y, Schulick RD. Pancreatic cancer treatment: better, but a long way to go. Surg Today, 2020, 50(10): 1117-1125.
30. Kim HJ, Lee HN, Jeong MS, et al. Oncogenic KRAS: signaling and drug resistance. Cancers, 2021, 13(22): 5599. doi: 10.3390/cancers13225599.
31. Dai E, Han L, Liu J, et al. Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun, 2020, 11(1): 6339. doi: 10.1038/s41467-020-20154-8.
32. Hu S, Sechi M, Singh PK, et al. A novel redox modulator induces a GPX4-mediated cell death that is dependent on iron and reactive oxygen species. J Med Chem, 2020, 63(17): 9838-9855.
33. Song R, Li T, Ye J, et al. Acidity-activatable dynamic nanoparticles boosting ferroptotic cell death for immunotherapy of cancer. Adv Mater, 2021, 33(31): e2101155. doi: 10.1002/adma.202101155.
34. Liu S, Zhao X, Shui S, et al. PDTAC: targeted photodegradation of GPX4 triggers ferroptosis and potent antitumor immunity. J Med Chem, 2022, 65(18): 12176-12187.
35. Zhou A, Fang T, Chen K, et al. Biomimetic activator of sonodynamic ferroptosis amplifies inherent peroxidation for improving the treatment of breast cancer. Small, 2022, 18(12): e2106568. doi: 10.1002/smll.202106568.
36. 马里程, 农晓琳. 青蒿琥酯抗肿瘤作用机制研究进展. 中华肿瘤防治杂志, 2020, 27(11): 921-926.
37. Ooko E, Saeed ME, Kadioglu O, et al. Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine, 2015, 22(11): 1045-1054.
38. Song Z, Xiang X, Li J, et al. Ruscogenin induces ferroptosis in pancreatic cancer cells. Oncol Rep, 2020, 43(2): 516-524.
39. Zhao J, He B, Seshadri VD, et al. Anticancer effect of ruscogenin in B(a)P-induced lung cancer in mice via modulation of proinflammatory cytokines and mitochondrial enzymes. Appl Biochem Biotechnol, 2022, 194(12): 5862-5877.
40. Lv Y, Wu X, Chen J, et al. Ruscogenin attenuated tight junction injury and tumor migration in colorectal liver metastasis mice via regulating TRAP1. Transl Cancer Res, 2021, 10(3): 1470-1483.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research status and future prospect of ferroptosis in pancreatic cancer

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