Roles of the PI3K/Akt pathway and autophagy in TLR3 signaling-induced apoptosis and growth arrest of human prostate cancer cells

• Published in: Cancer Immunology, Immunotherapy Vol. 61; no. 5; pp. 667 - 676
• Main Authors: Harashima, Nanae, Inao, Tohko, Imamura, Ryu, Okano, Shinji, Suda, Takashi, Harada, Mamoru
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2012; Springer; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antineoplastic agents; Antitumor activity; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Autophagy - physiology; Biological and medical sciences; Breast cancer; c-Myc protein; Cancer Research; Caspases - metabolism; CDC2 Protein Kinase - metabolism; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Cells; Cytokines; Dephosphorylation; endosomes; Endosomes - drug effects; Endosomes - metabolism; Gynecology. Andrology. Obstetrics; Humans; Immune response; Immune system; Immunology; Immunotherapy; Kinases; Ligands; Male; Male genital diseases; Medical sciences; Medicine; Medicine & Public Health; Nephrology. Urinary tract diseases; Oncology; Original; Original Article; p53 protein; Phagocytosis; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Poly (I:C); Poly I-C - pharmacology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myb - metabolism; Signal transduction; Signal Transduction - drug effects; TLR3 protein; Toll-Like Receptor 3 - metabolism; Toll-like receptors; Tumor cell lines; Tumor Suppressor Protein p53 - metabolism; Tumors; Tumors of the urinary system; University faculty; Urinary tract. Prostate gland; Japan; Germany; Akt; Prostate cancer; Autophagy; TLR3; Apoptosis; Human; Urinary system disease; Prostate disease; Toll like receptor 3; Enzyme; Growth; Transferases; Akt protein kinase; Malignant tumor; 1-Phosphatidylinositol 3-kinase; Signal transduction; Treatment; Cell death; Immunotherapy; Male genital diseases; Tumor cell; Cancer
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-011-1132-1

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.