Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

Abstract

Cervical cancer is the second most common malignant tumour threatening women's health. In recent years, heavy-ion beam therapy is becoming a newly emerging therapeutic mean of cancer; however, radio-resistance and radiation-induced damage constitute the main obstacles for curative treatment of cervical cancer. Therefore, to identify the radiosensitizers is essential. Here, we investigated the effects of Wnt signalling pathway on the response of 12 C 6þ radiation in HeLa cells. XAV939, an inhibitor of Wnt signalling pathway, was added two hours before 12 C 6þ radiation. 12 C 6þ radiation inhibited the viability of HeLa cells in a time-dependent manner, and inhibiting Wnt signalling using XAV939 significantly intensified this stress. Meanwhile, 12 C 6þ radiation induced a significant increased cell apoptosis, G2/M phase arrest, and the number of c-H2AX foci. Supplementation with XAV939 significantly increased the effects induced by 12 C 6þ radiation alone. Combining XAV939 with 12 C 6þ irradiation, the expression of apoptotic genes (p53, Bax, Bcl-2) was significantly increased, while the expression of Wnt-related genes (Wnt3a, Wnt5a, b-catenin, cyclin D1 and c-Myc) was significantly decreased. Overall, these findings suggested that blockage of the Wnt/b-catenin pathway effectively sensitizes HeLa cells to 12 C 6þ irradiation, and it may be a potential therapeutic approach in terms of increasing the clinical efficacy of 12 C 6þ beams.

The effects of the Wnt/β‑catenin signaling pathway on apoptosis in HeLa cells induced by carbon ion irradiation

“…Moreover, it has been reported that the aberrant activation of canonical Wnt signaling is involved in the multistep pathogenesis and progression of cervical cancer (29,30). Previously, we demonstrated that Wnt signaling pathway inhibition enhances radiosensitivity in human cervical cancer HeLa cells (31). Thus, the Wnt/β-catenin signaling pathway is involved in the tumorigenesis of numerous cancers, indicating its potential value as a target for cancer treatment.…”

Targeting the Wnt/β-catenin signaling pathway in cancer

“…Tankyrase inhibitor, XAV939 and IWR-1 regulated AXIN by inhibiting Tankyrase 1 and Tankyrase 2 [64,65]. Treatment with XAV939 decreased the viability of EOC cell lines and increased radio-sensitivity in cervical cancer cells [66]. Furthermore, the tankyrase-specific inhibitor, JW74 and JW55 affects cell cycle progression and induced apoptosis and differentiation in osteosarcoma and colon carcinoma cells, respectively [67,68].…”

Wnt Signaling in Gynecologic Malignancies

“…XAV939 is a TNKS inhibitor that leads to decreased β-catenin-dependent transcription through its regulation of Axin [122,138]. XAV939 treatment decreases the viability of EOC cell lines and increases radiosensitivity in CC cells [27,32].…”

“…Specifically, Wnt signaling promotes metastasis and therapy resistance in ovarian cancer, plays a crucial role in tumorigenesis and recurrence in endometrial cancer, and participates in human papillomavirus (HPV) -related tumorigenesis and metastasis in cervical cancer [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. For all of these gynecologic malignancies, Wnt signaling is also being evaluated as a possible therapeutic target [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. In this review, we will discuss the Wnt signaling pathway as it is related to the development, progression, and treatment of gynecologic malignancies.…”