Identifying apoptosis-evasion proteins/pathways in human hepatoma cells via induction of cellular hormesis by UV irradiation.
Evading apoptosis is pivotal in both of carcinogenesis and resistance to anticancer therapy. We investigated the molecules and pathways of apoptosis evasion in human hepatoma cells by irradiating hepatoma cells with optimized UV (so-called "hormetic responses"). Proteins and pathways related to hormetic responses were identified via proteomic approaches followed by reconstruction of function-networks. Of the 2326 defined protein spots, 42 distinct proteins significantly changed their expression. Eleven hormetic response proteins (HINT1, PHB, CTSD, ANXA1, LGASL1, TPT1, NPM, PRDX2, UCHL1, CERK, and C1QBP) were involved in 5 death-regulatory pathways, including the p53-dependent apoptotic pathway, protein ubiquinization, cellular redox, calcium-mediated signaling pathway, and sphingomyelin-metabolism pathway. Knockdown of HINT1 expression via RNA interference increased tumor cell resistance to apoptosis induction, while silencing NPM, UCHL1, or CERK greatly sensitized tumor cells to apoptosis induction. In conclusion, NPM, UCHL1, and CERK act as apoptosis-evasion proteins that may serve as therapeutic targets for hepatoma. Silencing their expression would increase therapeutic efficacy, thereby reducing the corresponding doses and side-effects of anticancer therapy. This model of induction of cellular hormetic responses to identify apoptosis-evasion molecules/pathways via proteomic approaches can be applied to other modalities of anticancer therapy.
Hsieh
Sen-Yung
SY
Chang Gung Memorial Hospital, Taoyuan, Taiwan. siming@adm.cgmh.org.tw
Hsu
Chih-Yun
CY
He
Jung-Ru
JR
Liu
Chiung-Liang
CL
Lo
Shao-Jung
SJ
Chen
Ying-Ching
YC
Huang
Hui-Yu
HY
D000595:Amino Acid Sequence; D000704:Analysis of Variance; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism* / Q000528:radiation effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000528:radiation effects; D000091402:Prohibitins; D020543:Proteome / Q000378:metabolism / Q000528:radiation effects; D040901:Proteomics / Q000379:methods*; D034622:RNA Interference; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000528:radiation effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000090324:Tumor Protein, Translationally-Controlled 1; D014466:Ultraviolet Rays
D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C000717328:PHB protein, human; D000091402:Prohibitins; D020543:Proteome; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1