The WNT/β-catenin signaling inhibitor XAV939 enhances the elimination of LNCaP and PC-3 prostate cancer cells by prostate cancer patient lymphocytes in vitro

Abstract

Upregulated Wnt/β-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/β-catenin is, however, associated with either immunosuppression or immunostimulation. Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/β-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/β-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that 5 µM XAV939 inhibited β-catenin translocation to the nucleus in LNCaP cells and CD4+ BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 µM XAV939. Comparable results were obtained for PC-3 prostate cancer cells. These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/β-catenin signaling.

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

“…Currently, there are several ongoing clinical trials of Wnt signalling pathway inhibitors that have been used to restrain tumour growth. XAV939 is a small molecule TNKS inhibitor targeting Wnt signalling pathway, which inhibits the abnormal activation of Wnt/b-catenin without affecting the normal function of cells [21,22]. Therefore, XAV939 is considered as a potential adjuvant to radiotherapy.…”

“…The Wnt/b-catenin signalling is a highly evolutionary conserved pathway that is implicated in many vital biological processes, such as embryonic development, stem cell regeneration, tissue homeostasis and cell survival [18][19][20]. Studies have shown Wnt/b-catenin signalling is often upregulated in a variety of cancer, which endows cells with a stem-like phenotype that enhances self-renewal ability, multi-differential potential, and induces epithelial-to-mesenchymal transition of cancer cells [21]. Moreover, aberrant activation of canonical Wnt signalling is usually associated with cancer cell-elicited immunosuppression, metastasis, and increased cancer cell tolerance to chemo/ radiotherapy or hormonal therapy [21,22].…”

“…Studies have shown Wnt/b-catenin signalling is often upregulated in a variety of cancer, which endows cells with a stem-like phenotype that enhances self-renewal ability, multi-differential potential, and induces epithelial-to-mesenchymal transition of cancer cells [21]. Moreover, aberrant activation of canonical Wnt signalling is usually associated with cancer cell-elicited immunosuppression, metastasis, and increased cancer cell tolerance to chemo/ radiotherapy or hormonal therapy [21,22]. Previous studies showed that activation of the Wnt/b-catenin signalling pathway may play a key role in the progression of cervical cancer following persistent HPV infection [23].…”

Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity

“…Recent studies have shown that treatment of melanoma or EG7 tumor-bearing mice with TNKS inhibitors XAV939 or JW55 markedly delayed tumor growth with augmented anti-tumor immunity (21,22,24). Likewise, recent ex vivo study on co-culture of LNCaP and PC-3 prostate cancer, cells with lymphocytes from prostrate cancer patients have shown that lymphocytes treated with XAV 939 are more potent in eliminating LNCaP and PC-3 prostate cancer cells (83). In addition, XAV 939 in combination with vaccines enhances anti-tumor immune responses by potently activating DCs in mice (83).…”

“…Likewise, recent ex vivo study on co-culture of LNCaP and PC-3 prostate cancer, cells with lymphocytes from prostrate cancer patients have shown that lymphocytes treated with XAV 939 are more potent in eliminating LNCaP and PC-3 prostate cancer cells (83). In addition, XAV 939 in combination with vaccines enhances anti-tumor immune responses by potently activating DCs in mice (83). Similarly, RNAi-mediated inhibition of β-catenin resulted in marked increase in antitumor immune response with reduced tumor burden in models of B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma, and renal adenocarcinoma (48).…”