title: Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells.
abstract: Radiotherapy of is well established and frequently utilized in prostate cancer (PCa) patients. However, recurrence following therapy and distant metastases are commonly encountered problems. Previous studies underline that, in addition to its therapeutic effects, ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of IR-induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. Here, we demonstrate that a plant flavonoid, silibinin can radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only strongly down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it strongly (p<0.001) reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. Most of the pro-angiogenic (VEGF, iNOS), migratory (MMP-2) and EMT promoting proteins (uPA, vimentin, N-cadherin) were up-regulated by IR in PCa cells. Interestingly, all of these invasive and EMT promoting actions of IR were markedly decreased by silibinin. Further, we found that potentiated effect was an end result of attenuation of IR-activated mitogenic and pro-survival signaling, including Akt, Erk1/2 and STAT-3, by silibinin.
authors.affiliation: Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India; School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Dhanya K
authors.initials: DK
authors.lastname: Nambiar
authors.affiliation: School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Paulraj
authors.initials: P
authors.lastname: Rajamani
authors.affiliation: Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India; School of Life Sciences, Central University of Gujarat, Gandhinagar, India. Electronic address: rana_singh@mail.jnu.ac.in.
authors.forename: Rana P
authors.initials: RP
authors.lastname: Singh
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000473:pathology*; D011839:Radiation, Ionizing; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: D043925:Angiogenesis Inducing Agents; D012838:Silymarin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077385:Silybin
keywords: Invasion; Ionizing radiation; Mitogenic signaling; Prostate cancer; Silibinin