Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting
| Autor: | Jinn‑Rung Kuo, Kun Goung Lai, Hung Sheng Shang, Chun‑Te Ho, Tsan Zon Liu, Jeng Fong Chiou, Yin Ju Chen |
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| Rok vydání: | 2016 |
| Předmět: |
GRP78
0301 basic medicine Cancer Research Activating transcription factor cisplatin survivin Biology 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Survivin medicine Bcl-2 Transcription factor Cisplatin GSH depletion Endoplasmic reticulum Articles 030104 developmental biology Oncology 030220 oncology & carcinogenesis Unfolded protein response Cancer research Signal transduction ER stress medicine.drug |
| Zdroj: | Oncology Letters |
| ISSN: | 1792-1082 1792-1074 |
| Popis: | Cisplatin is commonly recognized as a DNA-damaging drug; however, its versatile antitumor effects have been demonstrated to extend beyond this narrow functional attribute. The present study determined how cisplatin regulates alternative pathways and transcription factors to exert its additional antitumor actions. Cisplatin was observed to be able to trigger an endoplasmic reticulum stress response through aggravated nitrosative stress coupled to perturbed mitochondrial calcium (Ca2+) homeostasis, which substantially downregulated glucose-regulated protein (GRP) 78 expression by suppressing the cleavage of activating transcription factor (ATF) 6α (90 kDa) to its active 50 kDa subunit. Concomitantly, the ATF4-ATF3-C/emopamil binding protein homologous protein axis was activated by cisplatin, which triggered cellular glutathione (GSH) depletion by strongly inhibiting γ-glutamylcysteine synthetase heavy chain (γ-GCSh), a key enzyme in GSH biosynthesis. The present study also demonstrated that cisplatin substantially inhibited β-catenin, causing a marked downregulation of survivin and B-cell lymphoma (Bcl)-2. Taken together, the present results uncovered a novel mechanism of cisplatin that could simultaneously trigger the inhibition of three prominent antiapoptotic effector molecules (Bcl-2, survivin and GRP78) and effectively promote GSH depletion by inhibiting γ-GCSh. These newly discovered functional attributes of cisplatin can provide an avenue for novel combined therapeutic strategies to kill hepatocellular carcinoma cells effectively. |
| Databáze: | OpenAIRE |
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