The Role of Caspase-8, MLKL and RIPK1 in Iraqi Patients’ Women with Breast Cancer
DOI:
https://doi.org/10.23851/mjs.v36i1.1596Keywords:
Cancer, Breast cancer, Caspase-8, MLKL, RIPK1Abstract
Background: Breast cancer is the most common type of cancer that affects women’s breast tissue, leading to uncontrollably aberrant cell proliferation. Objective: This study aimed to investigate the role of Caspase-8, mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in pathogenicity of breast cancer (newly diagnosed and under treatment). Methods: A pilot study was conducted in the main medical hospital in Baghdad (Baghdad medical city-oncology teaching hospital). A total of 60 blood samples were collected from women with breast cancer aged 25-65 years old in addition to 28 blood samples were withdrawn from apparently healthy women aged match with patients. Samples were divided into three groups: 30 newly diagnosed patients suffered from breast cancer without treatment, 30 patients under treatment with chemotherapy (Adriamycin and Cyclophosphamide) (60 mg/m²), and 28 healthy control individuals. Three mL peripheral blood samples were withdrawn from each participant. The serum was isolated, and an ELISA assay was carried out to determine the serum level of the studied parameters. Results: The result showed a significant increase in the serum level of Caspase-8, MLKL and RIPK1 in all patients (newly diagnosed) versus control, and a significant decrease in the serum level of Caspase-8, MLKL and RIPK1 in all patients (under treatment) versus control, the results were (0.12±0.01, 1.11±0.18, 0.54±0.09), (2.35±0.28, 5.98±0.61, 0.72±0.14), and (0.11±0.01, 0.797±0.243, 0.129±0.030) ng/mL respectively. Also, the result showed a significant difference in the serum level of patients according to age, stage, grade and hormonal status of some understudied parameters. Conclusions: High serum levels of Caspase-8, MLKL and RIPK1 were found in Iraqi females with breast cancer with significant relation depending on grade, stage and hormonal status of breast cancer. While levels for Casp-8, MLKL, and RIPK1 were recorded in patients under treatment, it can be concluded that the studied marker may be considered a good predictor marker for therapeutic response in breast cancer patients.
Downloads
References
Republic of Iraq Ministry of Health and Environment Iraqi Cancer Board, “Annual report Iraqi cancer registry 2020,” 2020.
Link
A. M. S. Almohaidi, H. M. Al-Abassi, Z. J. Abdulkareem, and M. M. Al-Sayyid, "Sera level and polymorphism of interleukin-33 gene in Iraqi females patients with breast cancer," Ibn AL-Haitham Journal For Pure and Applied Sciences, vol. 34, no. 1, pp. 1-11, 2021.
CrossRef
M. Khalifa, "Impact of psychological distress in women upon coping with breast cancer: Coping with breast cancer," Iraqi National Journal of Nursing Specialties, vol. 35, no. 1, pp. 82-87, 2022.
CrossRef
A. Yousif, "Revision of some biomarkers with cytokines in breast cancer," Baghdad Science Journal, vol. 20, no. 1, pp. 26-31, 2023.
CrossRef
A. O. Salman, W. S. Mahood, and H. M. Al-Abassi, "HLA-G 14-bp insertion/deletion (In/Del) polymorphism in breast cancer Iraqi Arabian women," Indian Journal of Forensic Medicine & Toxicology, vol. 15, no. 3, pp. 1108-1116, 2021.
CrossRef
G.-e.-S. Chaudhry, A. Md Akim, Y. Y. Sung, and T. M. T. Sifzizul, "Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics," Frontiers in Pharmacology, vol. 13, p. 842 376, Aug. 2022.
CrossRef | PubMed
H. K. Ali and W. S. Mahood, "Expression of tansketolase TKTL1 in Iraqi breast cancer females," Journal of Population Therapeutics and Clinical Pharmacology, vol. 30, no. 8, pp. e55–e61, 2023.
CrossRef
C. Contadini, A. Ferri, C. Cirotti, D. Stupack, and D. Barilà, "Caspase-8 and tyrosine kinases: A dangerous liaison in cancer," Cancers, vol. 15, no. 13, p. 3271, 2023.
CrossRef | PubMed
S. Fulda, "Caspase-8 in cancer biology and therapy," Cancer Letters, vol. 281, no. 2, pp. 128-133, 2009.
CrossRef | PubMed
F. H. AL-Mafraji and M. A. Alaubydi, "Effect of some demographic changes on some oral immune aspects in periodontal disease patients," Ibn AL-Haitham Journal For Pure and Applied Sciences, vol. 36, no. 4, pp. 63-71, 2023.
CrossRef
M. Muzio, A. M. Chinnaiyan, F. C. Kischkel, K. O’Rourke, A. Shevchenko, J. Ni, C. Scaffidi, J. D. Bretz, M. Zhang, R. Gentz, M. Mann, P. H. Krammer, M. E. Peter, and V. M. Dixit, "FLICE, a novel FADD-Homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex," Cell, vol. 85, no. 6, pp. 817-827, 1996.
CrossRef | PubMed
I. Lavrik, A. Krueger, I. Schmitz, S. Baumann, H. Weyd, P. H. Krammer, and S. Kirchhoff, "The active caspase-8 heterotetramer is formed at the CD95 DISC," Cell Death & Differentiation, vol. 10, no. 1, pp. 144-145, 2003.
CrossRef | PubMed
D. W. Chang, Z. Xing, V. L. Capacio, M. E. Peter, and X. Yang, "Interdimer processing mechanism of procaspase-8 activation," The EMBO Journal, vol. 22, no. 16, pp. 4132-4142, 2003.
CrossRef | PubMed
G. Fianco, C. Contadini, A. Ferri, C. Cirotti, V. Stagni, and D. Barilà, "Caspase-8: A novel target to overcome resistance to chemotherapy in glioblastoma," International Journal of Molecular Sciences, vol. 19, no. 12, p. 3798, 2018.
CrossRef | PubMed
R. Mandal, J. C. Barrón, I. Kostova, S. Becker, and K. Strebhardt, "Caspase-8: The double-edged sword," Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, vol. 1873, no. 2, p. 188 357, 2020.
CrossRef | PubMed
H. S. Kim, J. W. Lee, Y. H. Soung, W. S. Park, S. Y. Kim, J. H. Lee, J. Y. Park, Y. G. Cho, C. J. Kim, S. W. Jeong, S. W. Nam, S. H. Kim, J. Y. Lee, N. J. Yoo, and S. H. Lee, "Inactivating mutations of caspase-8 gene in colorectal carcinomas," Gastroenterology, vol. 125, no. 3, pp. 708-715, 2003.
CrossRef | PubMed
Y. H. Soung, J. W. Lee, S. Y. Kim, J. Jang, Y. G. Park, W. S. Park, S. W. Nam, J. Y. Lee, N. J. Yoo, and S. H. Lee, "CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas," Cancer Research, vol. 65, no. 3, pp. 815-821, 2005.
CrossRef | PubMed
C. Li, A. M. Egloff, M. Sen, J. R. Grandis, and D. E. Johnson, "Caspase‐8 mutations in head and neck cancer confer resistance to death receptor‐mediated apoptosis and enhance migration, invasion, and tumor growth," Molecular Oncology, vol. 8, no. 7, pp. 1220-1230, 2014.
CrossRef | PubMed
R. A. Rasheed and H. M. Al-Abassi, "TGF-Beta3 (gene expression) as a new biological marker for diagnosing the gastric and colorectal cancer," Biochemical and Cellular Archives, vol. 21, no. 1, pp. 1539-1543, 2021.
CrossRef
L. Li, R. Feng, Y. Li, X. Yu, Y. Liu, Y. Zhao, and Z. Liu, "Caspase-8 mutants activate Nrf2 via phosphorylating SQSTM1 to protect against oxidative stress in esophageal squamous cell carcinoma," Free Radical Biology and Medicine, vol. 192, pp. 51-62, Nov. 2022.
CrossRef | PubMed
C. Zhan, M. Huang, X. Yang, and J. Hou, "MLKL: Functions beyond serving as the executioner of necroptosis," Theranostics, vol. 11, no. 10, pp. 4759-4769, 2021.
CrossRef | PubMed
J. Gautheron, M. Vucur, F. Reisinger, D. V. Cardenas, C. Roderburg, C. Koppe, K. Kreggenwinkel, A. T. Schneider, M. Bartneck, U. P. Neumann, A. Canbay, H. L. Reeves, M. Luedde, F. Tacke, C. Trautwein, M. Heikenwalder, and T. Luedde, "A positive feedback loop between RIP 3 and JNK controls non-alcoholic steatohepatitis," EMBO Molecular Medicine, vol. 6, no. 8, pp. 1062-1074, 2014.
CrossRef | PubMed
H. F. K. AL-Eqabi, S. A. A. H. A. A. Rahman, and H. M. ALabassi, "Dynamic role of IL-33, ST2 axis, SOD, leptin and nitric oxide in pathogenicity and disease progression in HBV chronic infection in Iraqi patients," Journal of Pharmaceutical Negative Results, vol. 13, no. 4, pp. 258-263, 2022.
CrossRef
U. Ros, A. Peña-Blanco, K. Hänggi, U. Kunzendorf, S. Krautwald, W. W.-L. Wong, and A. J. Garcı́a-Sáez, "Necroptosis execution is mediated by plasma membrane nanopores independent of calcium," Cell Reports, vol. 19, no. 1, pp. 175-187, 2017.
CrossRef | PubMed
Z. Liu, S. Choksi, H.-J. Kwon, D. Jiao, C. Liu, and Z.-g. Liu, "Tumor necroptosis-mediated shedding of cell surface proteins promotes metastasis of breast cancer by suppressing anti-tumor immunity," Breast Cancer Research, vol. 25, no. 1, p. 10, 2023.
CrossRef | PubMed
Z. Cai, A. Zhang, S. Choksi, W. Li, T. Li, X.-M. Zhang, and Z.-G. Liu, "Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration," Cell Research, vol. 26, no. 8, pp. 886-900, 2016.
CrossRef | PubMed
M. R. Abdullah and H. M. Alabassi, "The potential influence of immune modulatory molecules (TGF-βIII and CTLA-4) in pathogenicity of PCOS," Karbala International Journal of Modern Science, vol. 10, no. 3, pp. 363–375, 2024.
CrossRef
M. K. Khoury, K. Gupta, S. R. Franco, and B. Liu, "Necroptosis in the pathophysiology of disease," The American Journal of Pathology, vol. 190, no. 2, pp. 272-285, 2020.
CrossRef | PubMed
B. Tummers and D. R. Green, "Mechanisms of TNF-independent RIPK3-mediated cell death," Biochemical Journal, vol. 479, no. 19, pp. 2049-2062, 2022.
CrossRef | PubMed
M. C. Bonnet, D. Preukschat, P.-S. Welz, G. van Loo, M. A. Ermolaeva, W. Bloch, I. Haase, and M. Pasparakis, "The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation," Immunity, vol. 35, no. 4, pp. 572-582, 2011.
CrossRef | PubMed
S. Roychowdhury, M. R. McMullen, S. G. Pisano, X. Liu, and L. E. Nagy, "Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury," Hepatology, vol. 57, no. 5, pp. 1773-1783, 2013.
CrossRef | PubMed
D. Ofengeim, Y. Ito, A. Najafov, Y. Zhang, B. Shan, J. P. DeWitt, J. Ye, X. Zhang, A. Chang, H. Vakifahmetoglu-Norberg, J. Geng, B. Py, W. Zhou, P. Amin, J. B. Lima, C. Qi, Q. Yu, B. Trapp, and J. Yuan, "Activation of necroptosis in multiple sclerosis," Cell Reports, vol. 10, no. 11, pp. 1836-1849, 2015.
CrossRef | PubMed
G.-B. Koo, M. J. Morgan, D.-G. Lee, W.-J. Kim, J.-H. Yoon, J. S. Koo, S. I. Kim, S. J. Kim, M. K. Son, S. S. Hong, J. M. M. Levy, D. A. Pollyea, C. T. Jordan, P. Yan, D. Frankhouser, D. Nicolet, K. Maharry, G. Marcucci, K. S. Choi, H. Cho, A. Thorburn, and Y.-S. Kim, "Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics," Cell Research, vol. 25, no. 6, pp. 707-725, 2015.
CrossRef | PubMed
G.-W. He, C. Günther, V. Thonn, Y.-Q. Yu, E. Martini, B. Buchen, M. F. Neurath, M. Stürzl, and C. Becker, "Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice," Journal of Experimental Medicine, vol. 214, no. 6, pp. 1655-1662, 2017.
CrossRef | PubMed
I. Kostova, R. Mandal, S. Becker, and K. Strebhardt, "The role of caspase-8 in the tumor microenvironment of ovarian cancer," Cancer and Metastasis Reviews, vol. 40, no. 1, pp. 303-318, 2020.
CrossRef | PubMed
C. Y. Kadam and S. A. Abhang, "Apoptosis markers in breast cancer therapy," in Advances in Clinical Chemistry, vol. 74, pp. 143-193, 2016.
CrossRef | PubMed
L. Sun, H. Wang, Z. Wang, S. He, S. Chen, D. Liao, L. Wang, J. Yan, W. Liu, X. Lei, and X. Wang, "Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase," Cell, vol. 148, no. 1, pp. 213-227, 2012.
CrossRef | PubMed
A.-K. Knuth, S. Rösler, B. Schenk, L. Kowald, S. J. van Wijk, and S. Fulda, "Interferons transcriptionally up-regulate MLKL expression in cancer cells," Neoplasia, vol. 21, no. 1, pp. 74-81, 2019.
CrossRef | PubMed
J. Y. Baik, Z. Liu, D. Jiao, H.-J. Kwon, J. Yan, C. Kadigamuwa, M. Choe, R. Lake, M. Kruhlak, M. Tandon, Z. Cai, S. Choksi, and Z.-g. Liu, "ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer," Nature Communications, vol. 12, no. 1, p. 2666, 2021.
CrossRef | PubMed
D. Ofengeim and J. Yuan, "Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death," Nature Reviews Molecular Cell Biology, vol. 14, no. 11, pp. 727-736, 2013.
CrossRef | PubMed
F. Li, H. Sun, Y. Yu, N. Che, J. Han, R. Cheng, N. Zhao, Y. Guo, C. Huang, and D. Zhang, "RIPK1-dependent necroptosis promotes vasculogenic mimicry formation via eIF4E in triple-negative breast cancer," Cell Death & Disease, vol. 14, no. 5, p. 335, 2023.
CrossRef | PubMed
S. Fulda, "Targeting apoptosis signaling pathways for anticancer therapy," Frontiers in Oncology, vol. 1, Aug. 2011.
CrossRef | PubMed
A. De Blasio, R. Di Fiore, M. Morreale, D. Carlisi, R. Drago-Ferrante, M. Montalbano, C. Scerri, G. Tesoriere, and R. Vento, "Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231," International Journal of Oncology, vol. 48, no. 6, pp. 2339-2348, 2016.
CrossRef | PubMed
K. H. Alkashaf and S. I. Mohammed, "Impact of clinical pharmacist intervention on chemotherapy knowledge, attitude, and practice among breast cancer women," Journal of the Faculty of Medicine Baghdad, vol. 66, no. 1, pp. 103-109, 2024.
CrossRef
S. Martens, J. Bridelance, R. Roelandt, P. Vandenabeele, and N. Takahashi, "MLKL in cancer: more than a necroptosis regulator," Cell Death & Differentiation, vol. 28, no. 6, pp. 1757-1772, 2021.
CrossRef | PubMed
F. Karami-Tehrani, A. R. Malek, Z. Shahsavari, and M. Atri, "Evaluation of RIP1K and RIP3K expressions in the malignant and benign breast tumors," Tumor Biology, vol. 37, no. 7, pp. 8849-8856, 2016.
CrossRef | PubMed
K. Jamal, “Targeting RIPK1 ubiquitylation to promote anti-tumour immunity,” Ph.D. dissertation, Institute of Cancer Research (University Of London), 2019.
Link
X. Qiu, M. Zhuang, Z. Lu, Z. Liu, D. Cheng, C. Zhu, and J. Liu, "RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs," Journal of Translational Medicine, vol. 17, no. 1, p. 135, 2019.
CrossRef | PubMed
M. Jiang, L. Qi, L. Li, Y. Wu, D. Song, and Y. Li, "Caspase‐8: A key protein of cross‐talk signal way in 'PANoptosis' in cancer," International Journal of Cancer, vol. 149, no. 7, pp. 1408-1420, 2021.
CrossRef | PubMed
S. Park, J. Kim, Y. Cho, S. Ahn, G. Kim, D. Hwang, Y. Chang, S. Ha, Y. Choi, M. H. Lee, H. Han, S. Kim, S. I. Kim, and H. Lee, "Promotion of tumorigenesis by miR‐1260b-targeting CASP8: Potential diagnostic and prognostic marker for breast cancer," Cancer Science, vol. 113, no. 6, pp. 2097-2108, 2022.
CrossRef | PubMed
Q. Yao, W. Wang, J. Jin, K. Min, J. Yang, Y. Zhong, C. Xu, J. Deng, and Y. Zhou, "Synergistic role of Caspase-8 and Caspase-3 expressions: Prognostic and predictive biomarkers in colorectal cancer," Cancer Biomarkers, vol. 21, no. 4, pp. 899-908, 2018.
CrossRef | PubMed
Downloads
Key Dates
Received
Revised
Accepted
Published
Data Availability Statement
None.
Issue
Section
License
Copyright (c) 2025 Mays Najem Al-Adilee, Hazima Mossa Al-Abassi
This work is licensed under a Creative Commons Attribution 4.0 International License.
(Starting May 5, 2024) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution (CC-BY) 4.0 License that allows others to share the work with an acknowledgement of the work’s authorship and initial publication in this journal.
How to Cite
