| Summary: | 碩士 === 慈濟大學 === 生命科學系碩士班 === 99 === Cellular senescence is an important tumor suppressor mechanism response to
telomere erosion, DNA damage and oncogenic stimuli. Recent studies discovered that
despite the beneficial effects of cellular senescence, senescent cells can also exert
harmful effects on the tissue microenvironment. Senescent cells exhibit expression of
senescence-associated secretory phenotype (SASP) factors, which increase the
secretion of inflammatory factors that are able to stimulate tumor progression. Securin
is considered to be oncogene that is highly expressed in many tumors that regulates
cell proliferation and tumor formation. Our previous study showed that depletion of
securin induced senescence after irradiation and enhanced radio-sensitivity in human
cancer cells regardless of functional p53 expression. However, the molecular
mechanisms and beneficial or deleterious bystander effects of radiation-induced
senescent MCF-7 and securin-knockdown MDA-MB-231 human breast cancer cells
remain unknown. In this study, we found that activation of ataxia telangiectasia
mutated (ATM) induced by radiation led to senescence through checkpoint kinase 2
(Chk2) activation in both MCF-7 and securin-knockdown MDA-MB-231-2A breast
cancer cells. Furthermore, radiation induced senescence through reactive oxygen
species (ROS), activation of ATM-PI3K/AKT and p38 pathways. Moreover, the
conditioned medium (CM) from radiation-induced senescent human breast cancer cells induced invasion and migration of human breast cancer, stroma and human
umbilical vein endothelial cells (HUVECs) cells, but inhibited proliferation of cancer
cells. We discovered that cytokine platelet-derived growth factor-BB (PDGF-BB) and
interlukin-6 (IL-6) promoted invasion and migration of cancer cells through
PI3K/AKT- and signal transducer and activator of transcription 3 (STAT3)-dependent
(for IL-6 only) pathways. Finally, we analyzed cytokines and chemokines in CM from
radiation-induced senescent cells by using cytokine array, and discovered that
tumor-suppressive and pro-inflammatory cytokines were expressed. Taken together,
our results demonstrate the deleterious effects of SASP factor secreted from
radiation-induced senescent human breast cancer cells with lower expression of
securin and securin knockdown may contribute to tumor recurrence.
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