Article
Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells
Author/s | Rodríguez Hernández, María A.
González, Raúl Rosa, Ángel J. de la Gallego, Paloma Ordóñez, Raquel Navarro Villarán, Elena Contreras Bernal, Laura Rodríguez Arribas, M. Cruz Díaz, Jesús de la |
Department | Universidad de Sevilla. Departamento de Genética |
Publication Date | 2018 |
Deposit Date | 2019-06-12 |
Published in |
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Abstract | Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) ... Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) stress, c-Jun-N-terminal kinase (JNK), Akt, and 5′AMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 hr) ER stress characterized by an increase of Ser51P-eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P-JNK1/2/JNK1/2, Thr172P-AMPKα, Ser413P-Foxo3a, Thr308P-AKt/AKt and Thr32P-Foxo3a/Foxo3a ratios, and reduction of Ser2481P-mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim EL, Beclin-1, Bcl-xL, Bcl-2, autophagy markers, and reduction of myeloid cell leukemia-1 (Mcl-1) expression. The progressive increase of CHOP expression, and reduction of Thr308P-AKt/AKt and Ser473P-AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim EL expression and caspase-3 activity (24 hr). Small interfering-RNA (si-RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase-3 in sorafenib-treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor-derived xenograft model. In conclusion, the early sorafenib-induced ER stress and regulation of JNK and AMPK-dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK-CHOP-dependent rise of Bim EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim EL expression profile might also be related to the tight balance between AKt- and AMPK-related signaling leading to Foxo3a-dependent BIM EL upregulation. |
Project ID. | BFU2016‐75352‐P
PI15/00034 PI13/ 00021 PI16/00090 PI14/01349 FPU16/05127 FPU12/01433 FPU13/01237 CTS-6264 PI-00025-2013 PI-0127-2013 PI-0198-2016 |
Citation | Rodríguez Hernández, M.A., González, R., Rosa, Á.J.d.l., Gallego, P., Ordóñez, R., Navarro Villarán, E.,...,Cruz Díaz, J.d.l. (2018). Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells. Journal of Cellular Physiology, 234 (1), 692-708. |
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