Roles of the PI3K/Akt pathway and autophagy in TLR3 signaling-induced apoptosis and growth arrest of human prostate cancer cells |
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Authors: | Nanae?Harashima Tohko?Inao Ryu?Imamura Shinji?Okano Takashi?Suda Email author" target="_blank">Mamoru?HaradaEmail author |
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Institution: | (1) Department of Immunology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan;(2) Department of Surgery, Shimane University Faculty of Medicine, Shimane, Japan;(3) Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;(4) Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; |
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Abstract: | Toll-like receptors (TLRs) are widely expressed in immune cells and play a crucial role in many aspects of the immune response.
Although some types of TLRs are also expressed in cancer cells, the effects and mechanisms of TLR signaling in cancer cells
have not yet been fully elucidated. In the present study, we analyzed the effects of polyinosinic-polycytidylic acid poly(I:C)],
a TLR3 ligand, on three TLR3-expressing human prostate cancer cell lines (LNCaP, PC3, and DU145). We then further characterized
the underlying mechanisms, focusing on the poly(I:C)-sensitive LNCaP cell line. Poly(I:C) significantly reduced the viability
of LNCaP cells TLR3 and endosome dependently. One mechanism for the antitumor effect was caspase-dependent apoptosis, and
another mechanism was poly(I:C)-induced growth arrest. Cell survival and proliferation of LNCaP cells depended on the PI3K/Akt
pathway, and PI3K/Akt inhibitors induced apoptosis and growth arrest similar to poly(I:C) treatment. Additionally, poly(I:C)
treatment caused dephosphorylation of Akt in LNCaP cells, but transduction of the constitutively active form of Akt rendered
LNCaP cells resistant to poly(I:C). Immunoblot analysis of proliferation- and apoptosis-related molecules in poly(I:C)-treated
LNCaP cells revealed participation of cyclinD1, c-Myc, p53, and NOXA. Interestingly, poly(I:C) treatment of LNCaP cells was
accompanied by autophagy, which was cytoprotective toward poly(I:C)-induced apoptosis. Together, these findings indicate that
TLR3 signaling triggers apoptosis and growth arrest of LNCaP cells partially through inactivation of the PI3K/Akt pathway
and that treatment-associated autophagy plays a cytoprotective role. |
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