Key Takeaways & Executive Findings
- •• CD40 ligation promotes autophagosome formation and autophagic flux in cervical cancer cells, enhancing radiosensitivity. • The mechanism involves ERK-mediated upregulation of ATG13 via p53, linking CD40 signaling to autophagy regulation. • This study provides novel evidence that CD40 pathway activation can sensitize cervical cancer cells to radiotherapy. • Findings suggest potential therapeutic strategy combining CD40 activation with radiotherapy for cervical cancer treatment.
Abstract
CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, plays an important role not only in the immune system but also in tumor progression. CD40 ligation reportedly promotes autophagy in immune cells. However, the effects of CD40 ligation on autophagy and its mechanism in solid tumor cells are still unclear. In this study, we find that CD40 ligation promotes autophagosome formation and consequently promotes autophagic flux in cervical cancer cells. Mechanistically, this effect relies on ERK contributing to CD40 ligation-induced ATG13 upregulation by p53. Furthermore, we demonstrate that CD40 ligation-induced autophagy increases the radiosensitivity of cervical cancer cells. Taken together, our results provide new evidence for the involvement of the CD40 pathway in autophagy and radiotherapy in cervical cancer cells.
1. Introduction
CD40 is expressed not only on normal B lymphocytes and antigen-presenting cells but also on the surface of epithelioid tumors (cervical cancer, ovarian cancer, lung cancer, bladder cancer, and liver cancer) and hematological tumors [1,2]. CD40L (CD154), a type II membrane protein, is a ligand of CD40 that can be divided into two types, soluble and membrane-bound, both of which can exert their biological effects after binding to CD40 [3]. CD40 can form homotrimers under the stimulation of CD40L or combine with other members of the TNFR family to form heterotrimers. Polymerized CD40 can be autophosphorylated to recruit downstream signal molecules, which activate the PI3K-AKT, Ras-Raf-MEK-ERK and STAT3 signaling pathways to regulate gene expression, thus playing important roles in humoral and cell-mediated immune responses and in the development of tumors. Studies have shown that CD40 activation can inhibit the survival of many kinds of tumor cells, such as B-cell lymphoma, multiple myeloma, bladder cancer, ovarian cancer, breast cancer, skin cancer and cervical cancer cells, and improve the sensitivity of tumor cells to drugs [4,5], but its effect on cancer radiosensitivity is still unclear.
Cervical cancer is the fourth most common cancer among women worldwide, with approximately 604,000 new cases and 342,000 deaths in 2020, 90% of which are in developing countries [6]. At present, approximately 80% of invasive cervical cancer cases require radiotherapy, among which radiotherapy is the main treatment method for IB2-IIA non-surgical patients and IIB-IV patients [7]. Radiotherapy can induce autophagy, which can regulate radiosensitivity. However, the role of autophagy in radiotherapy for cervical cancer is controversial [8,9]. Some reports indicated that increased autophagy has a protective effect on cervical cancer cells. In contrast, other studies showed that the induction of autophagy can increase the radiosensitivity of cervical cancer cells, but the reason for this contradiction is not clear and may be related to the level of autophagy.
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Baocai Liu, Yadong Zhang, Quan Wang, Qian Wang, Zhixin Wang, Li Feng (2026). CD40 ligation-induced ERK activation leads to enhanced radiosensitivity in cervical carcinoma cells via promoting autophagy. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024229
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Frequently Asked Questions
What is the role of CD40 ligation in cervical cancer cells?
CD40 ligation promotes autophagosome formation and autophagic flux, which enhances the radiosensitivity of cervical cancer cells.
How does CD40 ligation induce autophagy in cervical cancer cells?
CD40 ligation activates ERK signaling, which leads to p53-mediated upregulation of ATG13, a key autophagy-related protein, thereby promoting autophagy.
What is the clinical significance of this study?
The findings suggest that combining CD40 activation with radiotherapy could be a potential therapeutic strategy to improve treatment outcomes in cervical cancer.
What are the key molecular mechanisms involved?
The key mechanisms involve the CD40-ERK-p53-ATG13 axis, which enhances autophagic flux and increases radiosensitivity.
What is the controversy regarding autophagy in cervical cancer radiotherapy?
Some studies show autophagy has a protective effect, while others indicate it increases radiosensitivity. This study clarifies that the level of autophagy may determine the outcome, with enhanced autophagy leading to increased radiosensitivity.
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