5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation
Open accessAbstract
5-Lipoxygenase (5LO) is involved in the production of leukotrienes and reactive oxygen species (ROS) from arachidonic acid. Its strong activation has been associated with several diseases like cancer and neurodegeneration. Here we show that 5LO activity increases during senescence-like growth arrest induced by oncogenic ras or culture history in both human and mouse embryo fibroblasts. Overexpression of 5LO promotes senescence-like growth arrest via a p53/p21-dependent pathway, and this occurs independently of telomerase activity. 5LO stabilizes p53 through phosphorylation at Ser15 and increases expression of the p53-transcriptional target p21. This is achieved by regulating ROS production. Indeed, ROS are increased in 5LO-arrested cells. Antioxidants and a low oxygen environment prevent 5LO-induced growth arrest. Finally, 5LO inhibition reduces the growth arrest induced by oncogenic ras or culture history and these effects are neutralized by the addition of exogenous ROS. These data link the 5LO pathway to oxidative crises of primary fibroblast and suggest that the ability of 5LO to induce senescence-like growth arrest may be important in the pathogenesis of 5LO-associated disorders.
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Ras-induced senescence can be inhibited by using antioxidants or growing cells in low-oxygen conditions.
“Ras-induced senescence can be inhibited by using antioxidants or growing cells in low-oxygen conditions (8, 25, 33, 51).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [8]
The section on 5LO expression and activity in oncogenic ras-mediated stasis reports that the antioxidant NAC diminished ROS and a senescence marker elicited by oncogenic Ras. The low-oxygen experiment, in the section on 5LO-induced stasis, instead tested cells expressing 5LO; it does not establish that low oxygen inhibits Ras-induced senescence. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCOX-2 inhibition similarly affects cell number, IL-6 secretion, EdU incorporation, and colony formation in oncogenic RAS-induced senescent cells.
“COX-2 inhibition similarly affected cell number, IL-6 secretion, EdU incorporation and colony formation in oncogenic RAS-induced senescent cells (Catalano et al., 2005; Serrano et al., 1997) (Figures S4B–S4F).”
From Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis (2021) · cites this paper as Catalano et al., 2005
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“Furthermore, 5-LO activity can trigger cellular senescence by stabilizing p53 via a ROS-dependent phosphorylation in fi bro-blasts thereby reducing cell proliferation and regulating the cellular lifespan [132].”
BackgroundSwindle, E. J., Coleman, J. W., DeLeo, F. R., & Metcalfe, D. D. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.10.7059 · Cited by 47 · see citing works
“ROS derived from 5-LO are involved in physiological responses in other cell types, including TNF- mediated ROS generation (55) and senescence-like growth arrest (56) in fibroblasts and mitogenic signaling in keratinocytes (57).”
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p53-Dependent Induction of Prostate Cancer Cell Senescence by the PIM1 Protein Kinase
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“OIS has been linked to DNA replicative stress, possibly through the induction of reactive oxygen species (81, 82) marked by aberrant premature termination of replication fork progression leading DNA breakage, the DDR response, and the induction of senescence (34, 83).”
Reactive oxygen species are generated through a BLT2-linked cascade in Ras-transformed cells
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Survival regulation of leukemia stem cells
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Cold atmospheric plasma as a potential tool for multiple myeloma treatment
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“As a secondary messenger, ROS can activate p53 expression, thereby regulating downstream targets of p53 [49, 50].”
BackgroundRole of Senescent Renal Cells in Pathophysiology of Diabetic Kidney Disease
Wiley, C. D. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01314-y · Cited by 38 · see citing works
“Finally, senescent cells release leukotrienes [19, 57], which promote pulmonary fibrosis in mouse models [19] and unilateral ureteral obstruction in mice [58].”
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Cross Talk Between Cellular Redox State and the Antiapoptotic Protein Bcl-2
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“- from xanthine oxidases (88), cyclooxygenases or prostaglandinendoperoxide synthase (PTGS) (55), the cytochrome P450 enzyme family (14), and nonheme lipoxygenases (21).”
Beyond leukotriene formation—The noncanonical functions of 5-lipoxygenase
Häfner, A., Kahnt, A. S., & Steinhilber, D. (2019) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2019.03.003 · Cited by 35 · see citing works
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Enhanced Antitumor Therapy by Inhibition of p21waf1 in Human Malignant Mesothelioma
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Bone Marrow Mesenchymal Stem Cell Transplantation Retards the Natural Senescence of Rat Hearts
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“6A, PDTC was able to induce the phosphorylation of Ser15, which has been previously reported to mediate the activation of p53 by ROS [19,20].”
BackgroundTargeted therapy of chronic myeloid leukemia
Sullivan, C., Peng, C., Chen, Y., Li, D., & Li, S. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.05.001 · Cited by 32 · see citing works
Increased expression of 5-lipoxygenase is common in clear cell renal cell carcinoma.
Faronato, M., Muzzonigro, G., Milanese, G., Menna, C., Bonfigli, A. R., Catalano, A., & Procopio, A. D. (2007) · PubMed · doi:10.14670/hh-22.1109 · Cited by 32 · see citing works
Torosyan, Y., Dobi, A., Naga, S., Mezhevaya, K., Glasman, M., Norris, C. F., Jiang, G., Mueller, G. P., Pollard, H. B., & Srivastava, M. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1574 · Cited by 28 · see citing works
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“As expected, the enforced expression of miR-29c induced the expression of p53 transcriptional targets p21 and p27 (Figure 3H, the left panel), the cyclin-dependent kinase inhibitors, due to the upregulation in p53 Ser15 phosphorylation [42].”
BackgroundHa, Y. J., Seul, H. J., & Lee, J. R. (2011) · Experimental & Molecular Medicine · doi:10.3858/emm.2011.43.2.012 · Cited by 26 · see citing works
Novel Therapeutic Agents Against Cancer Stem Cells of Chronic Myeloid Leukemia
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Lipids and the hallmarks of ageing: From pathology to interventions
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New hope in the horizon: cancer stems cells
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“Previously published work has suggested 5-HETE, a metabolite of 5-LOX, may have the capacity to induce a stasis-like phenotype in fibroblasts in a p53-dependent mechanism, although downstream intermediaries of 12-LOX and the contribution of NADPH-oxidase have not been explored in this context (13).”
BackgroundTelomeric DNA induces p53-dependent reactive oxygen species and protects against oxidative damage
Lee, M. S., Yaar, M., Eller, M. S., Rünger, T. M., Gao, Y. J., & Gilchrest, B. A. (2009) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2009.08.008 · Cited by 21 · see citing works
“The threemajor enzymes that catalyze the formation of cellular ROS are mitochondrial oxidases, primarily NADH oxidase [107], the cell surface-associated p53-regulated NAD(P)H oxidase [108] and 5-lipoxygenase that catalyzes ROS production from arachidonic acid [108–111].”
Life-history Constraints on the Mechanisms that Control the Rate of ROS Production
Aledo, J. C. (2014) · Current Genomics · doi:10.2174/1389202915666140515230615 · Cited by 20 · see citing works
“Thus, cytosolic enzymes such as cyclooxygenases [11], lypoxygenases [12] and flavoenzymes like xanthine oxidase [13] are able to produce ROS.”
BackgroundYin, S., Dong, Y., Li, J., Lü, J., & Hu, H. (2011) · Molecular Carcinogenesis · doi:10.1002/mc.20743 · Cited by 20 · see citing works
“It has been shown that an increase in the level of ROS can trigger senescence of humanfibroblasts [26] and senescence-like state in cancer cells [27].”
BackgroundHugo, C., Asante, I., Sadybekov, A., Katritch, V., & Yassine, H. N. (2024) · Antioxidants and Redox Signaling · doi:10.1089/ars.2024.0794 · Cited by 18 · see citing works
Lipoxygenases at the Intersection of Infection and Carcinogenesis
Amoah, A.-S., Pestov, N. B., Korneenko, T. V., Prokhorenko, I. A., Куракин, Г. Ф., & Barlev, N. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073961 · Cited by 18 · see citing works
“In drastic contrast to its role in tumor cells, ALOX5 in non-transformed cells promotes the p53/p21-induced growth arrest caused by forced expression of oncogenic Ras [202].”
BackgroundCellular Senescence, a Novel Area of Investigation for Metastatic Diseases
Faggioli, F., Velarde, M. C., & Wiley, C. D. (2023) · Cells · doi:10.3390/cells12060860 · Cited by 15 · see citing works
“The overexpression of 5-Lipoxygenase (5-LOX), which is known to promote cancer [148], also drives senescence-like growth arrest via a p53/p21dependent pathway [149].”
BackgroundBiological autoluminescence as a perturbance-free method for monitoring oxidation in biosystems
Vahalová, P., & Cifra, M. (2022) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2022.10.009 · Cited by 14 · see citing works
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“In addition to COX-2, LOXs have been suggested to be involved in generation of ROS [65,66].”
BackgroundAlox5 Blockade Eradicates JAK2V617F -Induced Polycythemia Vera in Mice
Chen, Y., Shan, Y., Lü, M., DeSouza, N. H., Guo, Z., Hoffman, R., Liang, A., & Li, S. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-2933 · Cited by 13 · see citing works
“Alox5 is involved in numerous physiological and pathological processes, including oxidative stress response, inflammation, and cancer (26-30).”
Moradi, F., Babashah, S., Sadeghizadeh, M., Jalili, A., Hajifathali, A., & Roshandel, H. (2019) · Europe PMC (PubMed Central) · doi:10.22038/ijbms.2019.31879.7666 · Cited by 13 · see citing works
“The signaling pathways like Hedgehog (Hh) (26, 27), Wnt/β-catenin (28), Notch (25), Alox5 (30, 31), Foxo (65-67), and Ras (62) may play roles in differentiation and survival of LSCs (35, 36).”
BackgroundRecent progress on targeting leukemia stem cells
Ma, X., Wei, L., Lei, Z., Chen, Y., Ding, Z., & Chen, Z. (2021) · Drug Discovery Today · doi:10.1016/j.drudis.2021.05.009 · Cited by 13 · see citing works
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“Since activation of oncogenes including K-ras and c-Myc induces senescencelike cell growth arrest in a variety of cell types [47, 48] and since we observed a short-lived G1 arrest induced by K-ras or c-Myc activation in Fanca−/− and Fancc−/− LSK cells (Figures 1D, 1E, S1E, S1F), we analyzed oncogeneinduced expression…”
BackgroundHematopoietic Stem Cells in Chronic Myeloid Leukemia
Chvez-Gonzlez, A., Avils-Vzquez, S., Lorenzana, D. M., & Mayani, H. (2013) · InTech eBooks · doi:10.5772/54651 · Cited by 12 · see citing works
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“Although it is well known that accelerated ROS leads to p53-dependent transcriptional activation of p21 (Gartel et al., 2001; Catalano et al., 2005), HaCaT cells harbor mutations in p53 gene, rendering transcriptionally defective protein, thereby avoiding regulation of its downstream targets such as p21 and Bax.”
BackgroundChung, S. W., Toriba, A., Chung, H. Y., Yu, B. P., Kameda, T., Tang, N., Kizu, R., & Hayakawa, K. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm252 · Cited by 12 · see citing works
“For example, RS generated by the 5-LO pathway was found to arrest growth of fibroblasts by activating p53 ( Catalano et al., 2005 ).”
BackgroundCDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway
Wang, X., Sipila, P., Si, Z., Rosales, J. L., Gao, X., & Lee, K. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04457-2 · Cited by 11 · see citing works
“Upon DNA damage and presence of other stressors that induce cellular senescence [25, 39].”
BackgroundInfluentialSenescence and Senescence-Related Disorders
Wang, Z. P., & Inuzuka, H. (2013) · InTech eBooks · doi:10.5772/56158 · Cited by 10 · see citing works
Park, M., Na, J., Kwak, S. Y., Park, S., Kim, H., Lee, S., Jang, W., Lee, S. B., Jang, W. I., Jang, H., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158390 · Cited by 11 · see citing works
“Activation of p53 signaling is also associated with cellular senescence [16,21,24].”
BackgroundEl‐Sisi, A. E., Sokar, S. S., Salem, T., & Abu-Risha, S. E.-S. (2013) · Toxicology and Industrial Health · doi:10.1177/0748233713485884 · Cited by 8 · see citing works
“Thus, it is reasonable to conclude that 5-LOX and its products may have a role in the process of carcinogenesis and tumor growth (Catalano et al., 2005; Romano and Claria, 2003).”
BackgroundOverexpression of 5-Lipoxygenase Increases the Neuronal Vulnerability of PC12 Cells to Aβ42
Wang, Z., Bin, Z. H. O. U., Mao, W., & Yin, M. (2011) · YAKUGAKU ZASSHI · doi:10.1248/yakushi.131.1843 · Cited by 8 · see citing works
Silva, E. F. E., Figueira, F. D. S., Lettnin, A. P., Salgado, M. T. S. F., Lopes, A. C., Rehbein, F., Kalil, S. J., & Votto, A. P. D. S. (2018) · Molecular Biology Reports · doi:10.1007/s11033-018-4569-x · Cited by 8 · see citing works
Leukemia Stem Cells in Chronic Myeloid Leukemia
Shan, Y., DeSouza, N. H., Qiu, Q., & Li, S. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-7342-8_9 · Cited by 7 · see citing works
Mitochondria-Targeted Catalase Does Not Suppress Development of Cellular Senescence during Aging
Mogck, B. A., Jezak, S. T., & Wiley, C. D. (2024) · Biomedicines · doi:10.3390/biomedicines12020414 · Cited by 6 · see citing works
“For example, NAD(P)H oxidases [40,41], lipoxygenases [42], and increased labile iron [43] have been shown to drive senescence.”
BackgroundChen, W., Wang, X., Huang, G., Qin, S., & Zhou, E. (2025) · Frontiers in Genetics · doi:10.3389/fgene.2025.1551450 · Cited by 6 · see citing works
“ALOX5 participates in cellular senescence by accelerating growth arrest through a p53/ p21-dependent pathway independently of telomerase activity (Catalano et al., 2005).”
Induction of p73, Δ133p53, Δ160p53, pAKT lead to neuroprotection via DNA repair by 5-LOX inhibition
Shekhar, S., & Dey, S. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-05127-5 · Cited by 6 · see citing works
“It is also reported that 5-LOX regulate p53 activity[4] and 56 p53 isoform ∆113p53/∆133p53 promotes DNA double-strand break repair to protect cell from 57 death and senescence in response to DNA damage[5].”
BackgroundThe Molecular Interplay Between p53-Mediated Ferroptosis and Non-Coding RNAs in Cancer
Punziano, C., Trombetti, S., Grosso, M., Tornesello, M. L., & Faraonio, R. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146588 · Cited by 5 · see citing works
“Of note, cellular senescence due to oncogenic Ras or culture injury involves ALOX5, which activates p53 and its transcriptional target p21 [206].”
Park, M. N. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512037 · Cited by 5 · see citing works
Genetic Variants in COX2 and ALOX Genes and Breast Cancer Risk in White and Black Women
Mongiovi, J. M., Hong, C., Zirpoli, G., Khoury, T., Omilian, A. R., Qin, B., Bandera, E. V., Yao, S., Ambrosone, C. B., & Gong, Z. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.679998 · Cited by 5 · see citing works
“Like the COX pathway, studies have shown that 5-lipoxygenase (5LOX) and itsmetabolites are upregulated inmultiple cancers and play a potential role in carcinogenesis (48).”
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“Enzymes that generate ROS such as 5-lipooxygenase (5LO) mediate Ras induced senescence [89].”
BackgroundAcute Immunological Phenotypes in Individuals with Traumatic Spinal Cord Injury
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Molecular mechanisms and recent advances in cellular senescence
Hussain, A., Tatar, M., & Gong, R. (2026) · Cell & Bioscience · doi:10.1186/s13578-026-01596-x · Cited by 2 · see citing works
“Leukotriene C4 is an essential mediator of ER stress and chemotherapy induced oxidative damage [412].”
Chronic myeloid leukemia as a stem cell-derived malignancy
Babashah, S., Rezaei–Tavirani, M., Azodi, M. Z., & Saki, N. (2012) · Archives of Advances in Biosciences · doi:10.22037/jps.v3i2.3479 · Cited by 2 · see citing works
- Authors
- Catalano, A., Rodilossi, S., Caprari, P., Coppola, V., & Procopio, A.
- Affiliations
- Marche Polytechnic University (IT)
- National Cancer Institute (US)
- Corresponding author
- Catalano, Alfonso
- Venue
- The EMBO Journal
- Published
- 2004-12-16
- Volume
- 24
- Issue
- 1
- Pages
- 170-179
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC544914
- OpenAlex
- W2068549027
- Cited by
- 123
- References
- 42
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 10 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 8 · 2018: 3 · 2017: 1 · 2016: 6 · 2015: 5 · 2014: 4 · 2013: 6 · 2012: 5
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Italiana per la Ricerca sul Cancro
- National Institutes of Health
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- 5-lipoxygenase, reactive oxygen species, p53 activation, p21, oncogenic Ras, culture history, oxidative stress, leukotrienes, arachidonic acid metabolism, embryonic fibroblasts, antioxidant defense, 5-lipoxygenase inhibition
- MeSH terms
- Animals, Arachidonate 5-Lipoxygenase, Cell Survival, Cells, Cultured, Fibroblasts, Humans, Phosphorylation, Signal Transduction, Transcriptional Activation, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Cellular Senescence, Reactive Oxygen Species, Mice, Knockout, Telomerase, Cell Proliferation, Mice
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