STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells
Open accessAbstract
Autophagy is one of the survival processes of cancer cells, especially in stressful conditions such as starvation, hypoxia and chemotherapeutic agents. However, its roles in tumor survival have not yet been fully elucidated. Here, we found for the first time that JAK2/STAT3 was activated in HeLa cells when they were starved or treated with rapamycin. STAT3 activation was associated with autophagic processes, because it was completely inhibited by 3-methyladenine, partially inhibited by knockdown of molecules associated with autophagic processes and blocked by antioxidants, DPI, a Nox inhibitor and knockdown of p22 phox, indicating that ROS generated by Nox that was activated during autophagic processes activated JAK2/STAT3 pathway. Activated STAT3 directly bound to IL6 promoter and increased IL6 mRNA and protein secretion. Finally, the conditioned media, which included IL6, from starved HeLa cells promoted cancer cell survival in both normal and starved conditions, confirmed by clonogenic, proliferation and cell death assays. These data together indicate that the autophagic process in cancer cells can contribute to their survival by JAk2/STAT3 activation and subsequent secretion of growth factors.
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IL-6 transcription is induced by a variety of stimuli, such as Toll-like receptor ligands, IL-1, TNFα, reactive oxygen species and zinc, and also depends on epigenetic regulation.
“IL-6 transcription is induced by a variety of stimuli, such as Toll-like receptor (TLR) ligands, IL-1, TNFα, reactive oxygen species (ROS) and zinc (Zn) and also depends on epigenetic regulation (33, 82, 84–86).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [82]
The section on STAT3 activation in starvation-induced autophagic cancer cells reports that ROS generated during starvation activates a pathway leading to IL6 induction; its promoter experiments also address IL6 transcription. Our copy does not support the other listed stimuli—TLR ligands, IL-1, TNFα and zinc—or the claim about epigenetic regulation. The paper’s finding is specifically in the context of starved cancer cells. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSTAT3 directly binds to the IL-6 promoter to induce IL-6 gene expression.
“STAT3 directly binds to the IL-6 promoter to induce IL-6 gene expression (82, 83).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [82]
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“ROS generated by NOX enzymes induced activation of Stat3 and autophagy of cancer cells [53].”
BackgroundSelf-citationGene expression of NOX family members and their clinical significance in hepatocellular carcinoma
Eun, H. S., Cho, S. Y., Joo, J. S., Kang, S. H., Moon, H. S., Lee, E. S., Kim, S. H., & Lee, B. S. (2017) · Scientific Reports · doi:10.1038/s41598-017-11280-3 · Cited by 58 · see citing works
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Oxidative metabolism in cancer
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“S3D), and various studies have reported that ROS can stimulate STAT3 and Akt activation in cells [29–32].”
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“IL-6 upregulate STAT3 activity through IL-6R/ JAK/STAT3 pathway, which increases the miR-93–5 p transcription in G-MDSCs and the enrichment of miR-93–5 p in GM-Exo.”
Wu, T., Ye, Y., Min, S., Zhu, J., Khobahy, E., Zhou, J. K., Yan, M., Hemachandran, S., Pathak, S., Zhou, X., et al. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38782 · Cited by 47 · see citing works
“Conversely, ROS activates STAT-3 and induces IL-6 production in cancer cells (46).”
BackgroundXin, D., Chu, X., Bai, X., Ma, W., Yuan, H., Qiu, J., Liu, C., Li, T., Zhou, X. J., Chen, W., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.05.007 · Cited by 47 · see citing works
You, D. J., Lee, H. Y., Taylor-Just, A. J., Linder, K. E., & Bonner, J. C. (2020) · Nanotoxicology · doi:10.1080/17435390.2020.1808105 · Cited by 47 · see citing works
“…or human cancer cells to induce the expression of pro-inflammatory cytokines such as IL-8, which serves to recruit neutrophils, and IL-6, which mediates several biological functions including cell proliferation, differentiation and immune cell function (Morgan and Liu, 2011; Yoon et al., 2010).”
BackgroundKushibiki, T., Tu, Y., Abu‐Yousif, A. O., & Hasan, T. G. (2015) · Scientific Reports · doi:10.1038/srep13114 · Cited by 46 · see citing works
“The levels of phosphorylated (i.e., activated) STAT-3 declined significantly following PDT, consistent with a previous report 47 (Supplementary Fig.”
InfluentialHassan, N. M. E., Said, E., & Shehatou, G. S. G. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119241 · Cited by 46 · see citing works
Wu, L., Tan, J., Wang, Z.-H., Chen, Y.-X., Gao, L., Liu, J., Shi, Y.-H., Endoh, M., & Yang, H. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.02.015 · Cited by 43 · see citing works
“ROS act as signaling molecules to activate JAK2 in various types of cell and disease models, leading to the phosphorylation of STAT3 [43, 44].”
BackgroundRMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription
Zhang, J., Pan, Y.-F., Ding, Z.-W., Yang, G.-Z., Tan, Y.-X., Yang, C., Jiang, T.-Y., Liu, L., Zhang, B., Han, T., et al. (2014) · Oncogene · doi:10.1038/onc.2014.84 · Cited by 42 · see citing works
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“The wet/dry method (Yoon et al., 2010) was used to measure brain edema.”
MethodLive and Let Die: Roles of Autophagy in Cadmium Nephrotoxicity
Thévenod, F., & Lee, W. (2015) · Toxics · doi:10.3390/toxics3020130 · Cited by 41 · see citing works
“ROS are generated by mitochondria [23] or possibly by NADPH oxidases in cancer cells [24] and appear to induce autophagy.”
BackgroundGao, S., Guo, K., Chen, Y., Zhao, J., Jing, R., Wang, L., Li, X., Hu, Z., Xu, N., & Li, X. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.655281 · Cited by 39 · see citing works
Uruski, P., Sepetowska, A., Konieczna, C., Pakuła, M., Wyrwa, M., Tussupkaliyev, A., Tykarski, A., Mikuła‐Pietrasik, J., & Książek, K. (2021) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-021-00287-4 · Cited by 38 · see citing works
Role of NADPH oxidase in the regulation of autophagy in cardiomyocytes
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NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1
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Nuclear JAK2: Form and Function in Cancer
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“…an important role in the regulation of other cancer cellular functions: for example, the predominant role of JAK2 in many types of cancer is tumorigenic via regulation of apoptosis (Yun et al., 2010), detachment-induced apoptosis-anoikis (Bretland et al., 2001), or autophagy (Yoon et al., 2010).”
BackgroundViruses, Autophagy Genes, and Crohn’s Disease
Hubbard, V. M., & Cadwell, K. (2011) · Viruses · doi:10.3390/v3071281 · Cited by 35 · see citing works
“A siRNA screen revealed that STAT3 limits autophagy in an mTOR independent fashion [167], and autophagy may be involved in STAT3 activation as well [168].”
BackgroundKong, E. Y., Cheng, S. H., & Yu, K. N. (2017) · Journal of Radiation Research · doi:10.1093/jrr/rrx101 · Cited by 35 · see citing works
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“Because ROS-dependent enhancement of STAT3 activation was reported in cancer cells [38], STAT3 may be involved in the ROS-dependent increase of c-maf expression.”
BackgroundSamidurai, M., Tarale, P., Janarthanam, C., Gomez-Estrada, C., Gordon, R., Zenitsky, G. D., Jin, H., Anantharam, V., Kanthasamy, A. G., & Kanthasamy, A. (2020) · Cells · doi:10.3390/cells9081831 · Cited by 31 · see citing works
“Additionally, elevated levels of ROS have been reported to be a crucial factor for STAT3 activation [107,108].”
BackgroundJin, X., Zhang, S., Ding, T., Zhao, P., Zhang, C., Zhang, Y., & Li, W. (2020) · Aging Cell · doi:10.1111/acel.13217 · Cited by 31 · see citing works
“…involved in stress-induced cellular senescence (Liu et al., 2017), and because ROS/STAT3 signaling pathway also regulates autophagy of cancer cells (Yoon et al., 2010), we reason that LMCD1 may function as an important converging point linking oxidative stress, testicular phagocytosis, and SC…”
BackgroundThe Role of Sex Differences in Autophagy in the Heart During Coxsackievirus B3-Induced Myocarditis
Koenig, A., Sateriale, A., Budd, R. C., Huber, S. A., & Buskiewicz, I. A. (2013) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-013-9525-5 · Cited by 31 · see citing works
“Augmented signaling of signal transducer and activator of transcription 3 (STAT3) in females, possibly concomitant with the induction of autophagy, was suggested to be an origin of sex differences in protection in mouse myocarditis model [79, 80].”
BackgroundKim, S. J., & Yoon, S. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.17 · Cited by 30 · see citing works
Self-citationEvaluation of intracellular lipid droplets viscosity by a probe with high fluorescence quantum yield
Lin, B., Li, Z., Lin, Y., Shu, Y., & Wang, J. (2023) · Analytica Chimica Acta · doi:10.1016/j.aca.2023.341776 · Cited by 29 · see citing works
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“Because STAT3 activation has been associated with autophagy processes [49], and JNK phosphorylates B-cell lymphoma 2 (Bcl-2) triggering its release from beclin 1 in response to various stimuli [50], the existence of sexual dimorphic autophagy signaling cascades is very likely.”
BackgroundResistance Training Attenuates Activation of STAT3 and Muscle Atrophy in Tumor-Bearing Mice
Testa, M. T. D. J., Cella, P. S., Marinello, P. C., Frajacomo, F., Padilha, C. D. S., Perandini, P. C., Moura, F., Duarte, J., Cecchini, R., Guarnier, F., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.880787 · Cited by 26 · see citing works
“Recently, some studies have also indicated that STAT3 participates in the process of autophagy during cancer (11, 12).”
BackgroundQin, D., Lee, W.-H., Gao, Z., Zhang, W., Peng, M., Sun, T., & Gao, Y. (2018) · Peptides · doi:10.1016/j.peptides.2018.01.009 · Cited by 27 · see citing works
“Excessive ROS production also induces the expression of interleukin (IL)-6 [14,15], thereby increasing the secretion of MMP-1 leading to collagen degradation [16].”
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Wang, J., Sun, Q., Zhang, J., Wang, H., & Liu, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042019 · Cited by 25 · see citing works
“In human cells, the JAK2/STAT3 signaling pathway has been shown to promote IL-6 expression [14,15].”
BackgroundFunctional Role of Nox4 in Autophagy
Forte, M., Palmerio, S., Yee, D., Frati, G., & Sciarretta, S. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-55330-6_16 · Cited by 25 · see citing works
- Authors
- Yoon, S., Woo, S. U., Kang, J. H., Kim, K., Kwon, M.-H., Park, S., Shin, H.-J., Gwak, H.-S., & Chwae, Y.-J.
- Affiliations
- Ajou University (KR)
- National Cancer Center (KR)
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2010-11-16
- Volume
- 6
- Issue
- 8
- Pages
- 1125-1138
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- OpenAlex
- W1991688383
- Cited by
- 163
- References
- 0
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 18 · 2020: 11 · 2019: 12 · 2018: 10 · 2017: 12 · 2016: 6 · 2015: 13 · 2014: 15 · 2013: 17 · 2012: 4
- FWCI
- 6.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Funders
- National Research Foundation
- Hallym University
- National Research Foundation of Korea
- Korea Science and Engineering Foundation (R13-2003-019)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- STAT3, JAK2/STAT3 signaling, reactive oxygen species, NADPH oxidase, interleukin-6, starvation, tumor cell survival, HeLa cells, rapamycin, 3-methyladenine, p22phox, conditioned medium, growth factor secretion
- MeSH terms
- Amino Acids, Autophagy, Base Sequence, Cell Survival, Enzyme Activation, Glucose, HeLa Cells, Humans, Molecular Sequence Data, Neoplasms, Promoter Regions, Genetic, Protein Binding, Transcription, Genetic, Interleukin-6, Gene Expression Regulation, Neoplastic, Culture Media, Conditioned, Reactive Oxygen Species, NADPH Oxidases, Sirolimus, Cell Proliferation, STAT3 Transcription Factor
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