Abstract
Combination of docetaxel, cisplatin and 5-FU, known as TPF, is an FDA-approved treatment for head and neck squamous cell carcinoma (HNSCC). Acquired chemo-resistance to TPF, a primary reason for non-responsiveness to the treatment and relapse of tumor is a major concern for treatment failure, especially in elder patients. In this study, we investigated the role of Interleukin-1 receptor-associated kinases (IRAK) mediated Toll-like receptor (TLR)—signaling in chemo-resistance using a cell line-based in-vitro TPF-resistant HNSCC model of laryngeal origin. TPF chemo-resistant state showed over-expression and phosphorylation of the active downstream kinases IRAK-1 and IRAK-4 along with enhanced proliferative potential, survival, stemness and metastatic capability as compared to the parent cell line. Pharmacological inhibition of IRAK-1 and -4 had a cytostatic effect on chemo-resistant cells and re-sensitized them to chemotherapy. The treatment also decreased the pro-oncogenic effects of the chemo-resistant cells. Our study provides insights into the pro-oncogenic role of amplified IRAK-1 and-4 mediated TLR signaling in TPF-resistant HNSCC. Pharmacological inhibition of IRAK-1 and-4 signaling is a promising therapeutic strategy for TPF-resistant HNSCC. It can also be used as a combination therapy or a chemo-drug sparing regimen in HNSCC.
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Data Availability
Data will be available on request to corresponding author.
Abbreviations
- HNSCC:
-
Head and neck squamous cell carcinoma
- HPV:
-
Human papillomavirus
- 5-FU:
-
5-Fluorouracil
- PD1:
-
Programmed cell death 1
- EGFR:
-
Epidermal growth factor receptor
- FDA:
-
Food and drugs administration
- PFS:
-
Progression-free survival
- TLR:
-
Toll-like receptor
- PAMPs:
-
Pathogen-associated molecular patterns
- DAMPs:
-
Damage-associated molecular patterns
- IRAK:
-
Interleukin-1 receptor-associated kinase
- TNBC:
-
Triple-negative breast cancer
- HCC:
-
Hepatocellular carcinoma
- PDAC:
-
Pancreatic ductal adenocarcinoma
- CRC:
-
Colorectal carcinoma
- NPC:
-
Nasopharyngeal carcinoma
- IC:
-
Inhibitory concentration
- Bcl-2:
-
B cell lymphoma-2
- Bcl-xL:
-
B cell lymphoma extra large
- MMP-2:
-
Matrix metalloproteinase-2
- ALDH1:
-
Aldehyde dehydrogenase-1
- IL-6:
-
Interleukin-6
- ANOVA:
-
Analysis of variance
- S.D.:
-
Standard deviation
- FSC:
-
Forward scatter
- SSC:
-
Side scatter
- CSCs:
-
Cancer stem cells
- MFI:
-
Mean fluorescence intensity
- EMT:
-
Epithelial-to-mesenchymal transition
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Acknowledgements
This research was funded by a grant from Gujarat State Biotechnology Mission (GSBTM) under the Financial Assistance Programme (Project ID-1393) to Ratika Srivastava. Humayara Khan was supported by research scholarships from The Maharaja Sayajirao University of Baroda, GSBTM and SHODH, Education Department, Govt. of Gujarat (Ref. ID-201901720067). Authors acknowledge The Department of Microbiology and Biotechnology Centre, The Maharaja Sayajirao University of Baroda, Gujarat, India and The Seeding labs, USA for infrastructure and instrumentation facilities.
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RS conceptualization, funding acquisition, methodology, visualization, project administration, data curation, resources, supervision, validation, writing-original draft, writing-review and editing. SNP and AM TCGA data mining analysis. HK investigation, validation, writing-original draft.
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Khan, H., Pandey, S.N., Mishra, A. et al. Suppression of TLR signaling by IRAK-1 and -4 dual inhibitor decreases TPF-resistance-induced pro-oncogenic effects in HNSCC. 3 Biotech 13, 14 (2023). https://doi.org/10.1007/s13205-022-03420-y
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DOI: https://doi.org/10.1007/s13205-022-03420-y