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Published on: June 14, 2019
IL1 Pathway in HPV-Negative HNSCC Cells Is an Indicator of Radioresistance After Photon and Carbon Ion Irradiation
Dinesh Kumar Tiwari1, Ricarda Hannen1, Kristian Unger2,3,4
1Department of Radiotherapy and Radiooncology, Philipps-University Marburg, Marburg, Germany.
Background:
Treatment of locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) with photon radiation is the standard of care but shows only moderate success. Alterations in response toward DNA DSB repair, apoptosis, and senescence are underlying determinants of radioresistance in the tumor cells. Recently, senescence and the associated secretory phenotype (SASP) came into the focus of research and raised the need to identify the tumor-promoting molecular mechanisms of the SASP. The aim of this project was to unravel more of this process and to understand the impact of the IL1 pathway, which plays a major role in SASP. The studies were performed for photon and 12C-ion irradiation, which strongly vary in their effect on radioresistance.
Materials And Methods:
A panel of five HPV-negative HNSCC cell lines was treated with photon and 12C-ion irradiation and examined for clonogenic survival, DNA DSB repair, and senescence. SASP and IL1 gene expressions were determined by RNA sequencing and activation of the IL1 pathway by ELISA. A functional impact of IL1A and IL1B was examined by specific siRNA knockdown.
Results:
Cell killing and residual DSBs were higher after 12C-ion than after photon irradiation. 12C-ion induced more senescence with a significant correlation with cell survival. The impact on radioresistance appears to be less than after photon irradiation. The expression of SASP-related genes and the IL1 pathway are strongly induced by both types of irradiation and correlate with radioresistance and senescence, especially IL1A and IL1B which exhibit excellent associations. Surprisingly, knockdown of IL1A and IL1B revealed that the IL1 pathway is functionally not involved in radioresistance, DSB repair, or induction of senescence.
Conclusions:
IL1A and IL1B are excellent indicators of cellular radioresistance and senescence in HNSCC cells without functional involvement in these processes. Clearly more research is needed to understand the molecular mechanisms of senescence and SASP and its impact on radioresistance.
Insights
Interleukin-1A (IL1A) and Interleukin-1B (IL1B) indicate radioresistance and senescence in head and neck cancer cells. However, these molecules do not functionally drive these processes, requiring further research into senescence and SASP mechanisms.
Area of Science:
- Oncology
- Radiation Biology
- Molecular Biology
Background:
- Standard photon radiation therapy for HPV-negative head and neck squamous cell carcinoma (HNSCC) has limited efficacy.
- Tumor cell responses to DNA damage repair, apoptosis, and senescence influence radioresistance.
- The senescence-associated secretory phenotype (SASP) and its tumor-promoting mechanisms, particularly the IL1 pathway, require further investigation.
Purpose of the Study:
- To investigate the role of the IL1 pathway in senescence and radioresistance in HNSCC.
- To compare the effects of photon and 12C-ion irradiation on HNSCC cell response.
- To understand the molecular mechanisms underlying SASP and its impact on treatment outcomes.
Main Methods:
- HNSCC cell lines were subjected to photon and 12C-ion irradiation.
- Assessed clonogenic survival, DNA double-strand break (DSB) repair, and senescence.
- Analyzed SASP and IL1 gene expression via RNA sequencing and ELISA; investigated IL1A/IL1B function using siRNA knockdown.
Main Results:
- 12C-ion irradiation induced greater cell killing, residual DSBs, and senescence compared to photon irradiation.
- SASP-related gene expression and IL1 pathway activation correlated with radioresistance and senescence.
- IL1A and IL1B showed strong associations with radioresistance and senescence but were not functionally involved upon knockdown.
Conclusions:
- IL1A and IL1B serve as reliable indicators of cellular radioresistance and senescence in HNSCC.
- The IL1 pathway is not functionally implicated in radioresistance, DSB repair, or senescence induction in these cells.
- Further research is essential to elucidate the complex molecular mechanisms of senescence, SASP, and their influence on radioresistance.
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