The Detergent-Soluble Cytoplasmic Pool of Survivin Suppresses Anoikis and Its Expression Is Associated with Metastatic Disease of Human Colon Cancer

et al. (2013) The Detergent-Soluble Cytoplasmic Pool of Survivin Suppresses Anoikis and Its Expression Is Associated with Metastatic Disease of Human Colon Cancer. PLoS ONE 8(2): e55710. doi:10.1371/journal.pone.0055710 The Detergent-Soluble Cytoplasmic Pool of Survivin Suppresses Anoikis and Its Expression Is Associated with Metastatic Disease of Human Colon Cancer Masato Hori 0 Tomoharu Miki 0 Mayumi Okamoto 0 Futoshi Yazama 0 Hiroaki Konishi 0 Hiroshi Kaneko 0 Fumio Shimamoto 0 Takahide Ota 0 Achim Temme 0 Masaaki Tatsuka 0 Srinivasa M. Srinivasula, IISER-TVM, India 0 1 Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima , Shoubara, Hiroshima , Japan , 2 Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan, 3 Department of Life Science, Medical Research Institute, Kanazawa Medical University , Uchinada, Ishikawa , Japan , 4 Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University Dresden , Dresden , Germany Survivin is a component of the chromosomal passenger complex (CPC) that is essential for accurate chromosome segregation. Interfering with the function of Survivin in mitosis leads to chromosome segregation errors and defective cytokinesis. Survivin contains a Baculovirus IAP Repeat (BIR) and therefore was originally classified as inhibitor of apopotosis protein (IAP), yet its role in apoptosis after cellular stress remains largely unknown. We demonstrate here, that Survivin predominantly suppresses anoikis, a form of programmed cell death induced by loss of cellular adhesion to extracellular matrix. Interestingly, cells ectopically overexpressing EGFP-Survivin showed after loss of cell-matrix-interaction a decreased expression of IkB-a. Subsequent subcellular protein fractionation and immunoprecipitation experiments revealed that XIAP interacts with detergent-soluble Survivin which is known to cooperatively activate NF-kB signaling. Examination of the expression levels of detergent soluble Survivin in colorectal cancer cell lines and in colorectal cancerous tissues revealed that detergent soluble cytoplasmic Survivin levels correlated inversely with anoikis susceptibility in colorectal cancer. Therefore, the detergent soluble cytoplasmic Survivin might be a promising predictive biomarker for lymph node and distant metastases of colorectal cancer. We conclude that an anti-apoptotic function of detergent-soluble Survivin in interphase cells experiencing anoikis is mediated at least via XIAP/IkB-a/NF-kB signaling. - Funding: This work was supported by grants from the Japan Society for the Promotion of Science (KAKENHI No. 21591730 for Masaaki Tatsuka) and Prefectural University of Hiroshima (Important Research Project, GAKUNAI KYODO KENKYU H-24 for Masaaki Tatsuka, Hiroaki Konishi, and Fumio Shimamoto), and Prefectural University of Hiroshima Graduate School of Comprehensive Scientific Research to Mayumi Okamoto and Guangying Qi (Research Associate Grant H-24). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. During cancer development, metastatic cells detach from neighboring tumor cells, acquire cell motility, invade and enter the lymph system or blood circulation, survive and form metastatic lesions. These steps involve many genes and pathways, and yet these biological processes are poorly understood despite many scientific approaches [1]. The identification of metastatic tumortargeting molecules for diagnostic and therapeutic procedures is still required. Survivin is a member of the chromosomal passenger protein complex (CPC) that is a key regulator of mitosis. Survivin and other CPC components, Aurora-B, inner centromere protein (INCENP), and Borealin (Dasra B) are essential for the CPC functions including kinetochore attachment error corrections and completion of cytokinesis [2]. Survivin contributes to the mitotic localization of the CPC and has been described to enhance Aurora-B kinase activity as shown in Xenopus laevis and S. pombe [3,4]. In early mitosis, phosphorylation of Histone H3 at threonine 3 mediated by Haspin and subsequent binding of Survivin to this site is critical for assembling CPC on kinetochores [5,6,7]. Survivin is periodically expressed during the cell cycle peaking in mitosis [8]. Previou studies have shown that Survivin expression is impaired by p53, and loss of p53 function, which is often observed in cancer cells, increases its transcription [9,10]. Indeed most cancer cells analyzed so far up-regulate Survivin [11,12] when compared to normal cells or adjacent tissues. In addition, in many human cancer cases, Survivin has been detected even during interphase [13,14]. Overexpression of Survivin is frequently found in colorectal cancer [15,16,17 (...truncated)