Identifying Apoptosis-Evasion Proteins/Pathways in Human Hepatoma Cells via Induction of Cellular Hormesis by UV Irradiation

Abstract

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.

Potential prognostic marker ubiquitin carboxyl-terminal hydrolase-L1 does not predict patient survival in non-small cell lung carcinoma

“…This caused endoplasmic reticulum stress in the neuroblastoma cells which eventually led to the initiation of cell death [38]. Likewise, the up-regulation of UCH-L1 in human hepatoma cells following low dose UV irradiation was reported to be involved in the regulation of cell death by inhibition of p53-mediated apoptosis; hence in both these cases UCH-L1 was demonstrated to be an "apoptosis-evading protein" [39], as in the present study.…”

Effects of Lead on the Morphology and Structure of the Nucleolus in the Root Tip Meristematic Cells of Allium cepa L.

“…Nucleophosmin, nucleolin and fibrillarin are major multifunctional nucleoproteins participating in rRNA processing and ribosome biogenesis [18]. Nucleophosmin, a 37-kDa phosphoprotein, plays a pivotal role in protecting cells from death in response to cell stress [45]. Various cellular activities have been attributed to it, including cell proliferation [46], nucleic acid binding, ribonuclease, molecular chaperone [47] and response to stress-stimuli [48].…”

Ceramide Kinase Contributes to Proliferation but not to Prostaglandin E₂ Formation in Renal Mesangial Cells and Fibroblasts

“…Apart from these preclinical findings, evidence for a key role of CerK in tumor progression was reported by Ruckhäberle et al [47], who demonstrated that high CerK expression in tumor tissues correlated with a worse prognosis in patients with estrogen receptor-negative breast cancer. Moreover, recent data also suggest that the CerK protein is upregulated as a hormetic response of hepatoma cells exposed to UV irradiation to evade apoptosis, which could be counteracted by CerK silencing [48]. Based on this observation, pharmacological inhibition of CerK was suggested as a new concept in hepatoma therapy.…”