IL-11 mediates the Radioresistance of Cervical Cancer Cells via the PI3K/Akt Signaling Pathway

Abstract

Cervical cancer is one of the most common malignant tumors in the female reproductive system. Radioresistance remains a significant factor that limits the efficacy of radiotherapy for cervical cancer. Interleukin‐11 (IL-11) has been reported to be upregulated in various types of human cancer and correlate with clinical stage and poor survival. However, the exact effects and mechanisms of IL-11 in the radioresistance of cervical cancer have not yet been defined. In this research, TCGA databases revealed that IL-11 expression was upregulated in cervical cancer tissues and was associated with clinical stages and poor prognosis in cervical cancer patients. We discovered that IL-11 concentration was significantly upregulated in radioresistant cervical cancer cells. Knocking down IL-11 in Hela cells could reduce clonogenic survival rate, decrease cell viability, induce G2/M phase block, and facilitate cell apoptosis. In contrast, Exogeneous IL-11 in C33A cells could upregulate clonogenic survival rate, increase cell viability, curb G2/M phase block, and cell apoptosis. Mechanistic investigations showed that radioresistance conferred by IL-11 was attributed to the activation of the PI3K/Akt signaling pathway. Altogether, our results demonstrate that IL-11 might be involved in radioresistance, and IL-11 may be a potent radiosensitization target for cervical cancer therapy.

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“…The PI3K/ AKT/mTOR signaling pathway is hyperactivated or altered in many cancer types (177). Inhibition of the pathway reduces tumor cell radioresistance (178,179). For example, dactolisib, a dual PI3K/ mTOR inhibitor, causes cell cycle arrest in the G2/M phase and improves the radiosensitivity of DU145 cell lines.…”

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“…pathways, but attenuates cell apoptosis only through the PI3K-dependent signaling pathway [33]. The expression of p-Akt and the apoptosis-related proteins Bcl-2 (antiapoptotic protein), Bcl-xl (anti-apoptotic protein), and Bax (pro-apoptotic protein) are downregulated in IL-11 knockdown cells, revealing that IL-11 activates the PI3K/Akt signaling pathway in the treatment of radiotherapy-resistant cervical cancer [32,34].…”

“…PI3K inhibitor and siRNA-STAT3 mitigate the expression of matrix metalloproteinase (MMP)-13 induced by rhIL-11, revealing the involvement of PI3K/AKT and JAK/STAT3 signal transduction pathways [ 32 ]. IL-11 increases cell proliferation via MEK- and PI3K-dependent signaling pathways, but attenuates cell apoptosis only through the PI3K-dependent signaling pathway [ 33 ]. The expression of p-Akt and the apoptosis-related proteins Bcl-2 (anti-apoptotic protein), Bcl-xl (anti-apoptotic protein), and Bax (pro-apoptotic protein) are downregulated in IL-11 knockdown cells, revealing that IL-11 activates the PI3K/Akt signaling pathway in the treatment of radiotherapy-resistant cervical cancer [ 32 , 34 ].…”

“…The expression of p-Akt and the apoptosis-related proteins Bcl-2 (anti-apoptotic protein), Bcl-xl (anti-apoptotic protein), and Bax (pro-apoptotic protein) are downregulated in IL-11 knockdown cells, revealing that IL-11 activates the PI3K/Akt signaling pathway in the treatment of radiotherapy-resistant cervical cancer [ 32 , 34 ]. IL-11 upregulates MMP-13 expression by activating PI3K, Akt, and AP-1 signaling pathways that subsequently enhances MMP-13-induced tumor metastasis [ 33 ]. Thus, IL-11 is involved in tumorigenesis via the PI3K/Akt pathway ( Fig.…”