title: Mechanical regulation of cancer cell apoptosis and autophagy: roles of bone morphogenetic protein receptor, Smad1/5, and p38 MAPK.
abstract: Mechanical forces induced by interstitial fluid flow in and surrounding tissues and by blood/lymphatic flow in vessels may modulate cancer cell invasion and metastasis and anticancer drug delivery. Our previous study demonstrated that laminar flow-induced shear stress induces G2/M arrest in tumor cells. However, whether shear stress modulates final cell fate remains unclear. In this study, we investigated the role of flow-induced shear stress in modulating the survival of four human tumor cell lines, i.e., Hep3B hepatocarcinoma cells, MG63 osteosarcoma cells, SCC25 oral squamous carcinoma cells, and A549 carcinomic alveolar basal epithelial cells. Laminar shear stress (LSS) ranging from 0.5 to 12dyn/cm(2) induced death of these four tumor cell lines. In contrast to LSS at 0.5dyn/cm(2), oscillatory shear stress (OSS) at 0.5±4dyn/cm(2) cannot induce cancer cell death. Both LSS and OSS had no effect on human normal hepatocyte, lung epithelial, and endothelial cells. Application of LSS to these four cell lines increased the percentage of cells stained positively for annexin V-FITC, with up-regulations of cleaved caspase-8, -9, and -3, and PARP. In addition, LSS also induced Hep3B cell autophagy, as detected by acidic vesicular organelle formation, LC3B transformation, and p62/SQSTM1 degradation. By transfecting with small interfering RNA, we found that the shear-induced apoptosis and autophagy are mediated by bone morphogenetic protein receptor type (BMPR)-IB, BMPR-specific Smad1 and Smad5, and p38 mitogen-activated protein kinase in Hep3B cells. Our findings provide insights into the molecular mechanisms by which shear stress induces apoptosis and autophagy in tumor cells.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan; Institute of Molecular and Cellular Biology, Department of Medical Science, National Tsing-Hua University, Hsinchu, Taiwan.
authors.forename: Sheng-Chieh
authors.initials: SC
authors.lastname: Lien
authors.affiliation: Biophotonics and Molecular Imaging Research Center, National Yang Ming University, Taipei, Taiwan.
authors.forename: Shun-Fu
authors.initials: SF
authors.lastname: Chang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Lee
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Wei
authors.affiliation: Institute of Molecular and Cellular Biology, Department of Medical Science, National Tsing-Hua University, Hsinchu, Taiwan.
authors.forename: Margaret Dah-Tsyr
authors.initials: MD
authors.lastname: Chang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. Electronic address: jychang@nhri.org.tw.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan. Electronic address: jjchiu@nhri.org.tw.
authors.forename: Jeng-Jiann
authors.initials: JJ
authors.lastname: Chiu
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: Apoptosis; Autophagy; BMP receptor; MAPK; Mechanical force; Smad1/5