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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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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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Acknowledgments

We thank Ms. Yasuko Moriyama for her technical assistance. We thank Dr. Davey RA for the mCAT-1 vector and Dr. Toshio Kitamura for the PLAT-E cells. This study was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (no. 18591449 to M. H., no. 23701074 to N. H.), and Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University.

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Authors and Affiliations

  1. Department of Immunology, Shimane University Faculty of Medicine, Izumo, Shimane, 693-8501, Japan

    Nanae Harashima, Tohko Inao & Mamoru Harada

  2. Department of Surgery, Shimane University Faculty of Medicine, Shimane, Japan

    Tohko Inao

  3. Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    Ryu Imamura & Takashi Suda

  4. Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shinji Okano

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  1. Nanae Harashima
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  2. Tohko Inao
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Correspondence to Mamoru Harada.

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Harashima, N., Inao, T., Imamura, R. et al. Roles of the PI3K/Akt pathway and autophagy in TLR3 signaling-induced apoptosis and growth arrest of human prostate cancer cells. Cancer Immunol Immunother 61, 667–676 (2012). https://doi.org/10.1007/s00262-011-1132-1

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  • DOI: https://doi.org/10.1007/s00262-011-1132-1

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