title: Apoptosis signals in lymphoblasts induced by focused ultrasound.
abstract: We investigated the effects of focused ultrasound (FUS) on specific molecular signaling and cellular response in three closely related human Tk6 lymphoblast cell lines that differed only in their p53 status. The applied ultrasound parameters fell between the physical dose range, which is safely used in medical diagnostics (peak pressure<0.1 MPa) and that used for high-energy FUS thermal ablation therapy (peak pressure>10 MPa). Based on cDNA microarrays and protein analysis, we found that FUS at the intermediate peak pressure of 1.5 MPa induced a complex signaling cascade with upregulation of proapoptotic genes [e.g., p53, p21, Thy1 (CD 90)]. Simultaneously, FUS downregulated cellular survival components (e.g., bcl-2, SOD). The p53 status was important for the reaction of the cells to ultrasound. Apoptosis and G1 arrest were induced primarily in p53+ cells, while p53- cells showed less apoptosis but exhibited G2 arrest. Likewise, the proliferation of lymphoblasts was much more strongly inhibited in p53+ than in p53- cells. Microarray analysis further demonstrated an upregulation of genes involved in oxidative stress (e.g., ferritin), suggesting that indirect sonochemical effects via reactive oxygen species play a causative role in the interaction of ultrasound with lymphoblasts. An important characteristic of FUS in therapeutic ultrasound applications is its ability to be administered to the human body in a targeted manner while sparing intermediate tissues. Therefore, our data indicate that this noninvasive, mechanical wave transmission, which is free of ionizing radiation, has the potential to specifically induce localized cell signals and apoptosis.
authors.affiliation: Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.forename: Sophie
authors.initials: S
authors.lastname: Domhan
authors.forename: Juergen W
authors.initials: JW
authors.lastname: Jenne
authors.forename: Mazin
authors.initials: M
authors.lastname: Hallaj
authors.forename: Giorgio
authors.initials: G
authors.lastname: Dell'Aqua
authors.forename: Martina
authors.initials: M
authors.lastname: Mueckenthaler
authors.forename: Alexandra
authors.initials: A
authors.lastname: Richter
authors.forename: Heather
authors.initials: H
authors.lastname: Martin
authors.forename: Juergen
authors.initials: J
authors.lastname: Debus
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Ansorge
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006801:Humans; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014465:Ultrasonics
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53