A novel interaction of nucleophosmin with BCL2-associated X protein regulating death evasion and drug sensitivity in human hepatoma cells
| Autor: | Yow-Fu Tsai, Shiu-Fen Huang, Benjamin Yat-Ming Yung, Kuo-Yang Lin, Tse-Chin Chen, Tong-Hong Wang, Shao-Jung Lo, Li-Ching Fan, Yu-Jr Lin, Sen-Yung Hsieh, Hsiao-Ling Huang, Hsuan Liu, Chee-Jen Chang |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Programmed cell death Cytoplasm Carcinoma Hepatocellular Antineoplastic Agents Apoptosis Mitochondria Liver Kaplan-Meier Estimate medicine.disease_cause Bcl-2-associated X protein Cell Line Tumor medicine Gene silencing Humans bcl-2-Associated X Protein Cisplatin Nucleophosmin integumentary system Hepatology biology Liver Neoplasms Nuclear Proteins Middle Aged Molecular biology digestive system diseases Up-Regulation Treatment Outcome Cell culture Drug Resistance Neoplasm Mutation biology.protein Cancer research Female Tumor Suppressor Protein p53 Carcinogenesis medicine.drug |
| Zdroj: | Hepatology (Baltimore, Md.). 57(5) |
| ISSN: | 1527-3350 |
| Popis: | Death evasion is crucial for both carcinogenesis and resistance to anticancer therapies. Recently, we identified nucleophosmin (NPM) as a key factor counteracting death stimuli in human hepatocellular carcinoma (HCC) cells. Here we report the identification of a novel NPM-BCL2-associated X protein (BAX) pathway orchestrating death evasion in human HCC cells. Silencing of NPM expression significantly sensitized HCC cells—particularly those bearing inactivated p53 gene (Huh7, Hep3B, and Mahlavu)—to ultraviolet irradiation, mitomycin C, doxorubicin, cisplatin, sorafenib, and lapatinib. This sensitizing effect was not changed further, as p53 expression had been simultaneously silenced. Following cell stress, NPM and BAX were induced and exported out of the nucleoli and nucleus, respectively. BAX was translocated to cytoplasm in cells with relatively high NPM level, or accumulated in the mitochondria in cells with relatively low NPM level and undergoing apoptosis. Subcellular fractionation revealed that silencing of NPM expression greatly enhanced mitochondrial translocation and oligomerization of BAX in Huh7 and Mahlavu cells. In situ proximity ligation assays and reciprocal co-immunoprecipitation revealed a direct interaction between NPM and BAX in the cytoplasm. Silencing of BAX expression abolished the sensitization effect exerted by silencing of NPM in HCC cells. Clinically, up-regulation of NPM was significantly associated with advanced tumor stage and poor prognosis. Conclusion: By directly blockading BAX mitochondrial translocation and activation, NPM helps human HCC cells evade death induction independently of p53-mediated cell death. Silencing of NPM significantly sensitized HCC cells to anticancer therapies. NPM is a potential cotarget in combination with other therapies for HCC, particularly those that harbor inactivated p53 gene. Our findings are of clinical significance because NPM up-regulation and p53 mutations are usually found in advanced human cancers, including HCC. (HEPATOLOGY 2013) |
| Databáze: | OpenAIRE |
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