Enhancement of paclitaxel-induced breast cancer cell death via the glycogen synthase kinase-3β-mediated B-cell lymphoma 2 regulation

• Published in: BMB reports Vol. 49; no. 1; pp. 51 - 56
• Main Authors: Noh, Kyung Tae, Cha, Gil Sun, Kang, Tae Heung, Cho, Joon, Jung, In Duk, Kim, Kwang-Youn, Ahn, Soon-Cheol, You, Ji Chang, Park, Yeong-Min
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Society for Biochemistry and Molecular Biology 01.01.2016; 생화학분자생물학회
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Cytochromes c - metabolism; DNA Fragmentation - drug effects; Enzyme Activation - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; MCF-7 Cells; Membrane Potential, Mitochondrial - drug effects; Mitochondria - metabolism; Paclitaxel - pharmacology; Protein Stability - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Ubiquitination; 화학
• ISSN: 1976-6696; 1976-670X; 1976-670X
• DOI: 10.5483/BMBRep.2016.49.1.102

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine protein kinase that is known to mediate cancer cell death. Here, we show that B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein, is regulated by GSK-3β and that GSK-3β-mediated regulation of Bcl-2 is crucial for mitochondrial-dependent cell death in paclitaxel-stimulated cells. We demonstrate that MCF7 GSK-3β siRNA cells are more sensitive to cell death than MCF7 GFP control cells and that in the absence of GSK-3β, Bcl-2 levels are reduced, a result enhanced by paclitaxel. Paclitaxel-induced JNK (c-Jun N-terminal kinase) activation is critical for Bcl-2 modulation. In the absence of GSK-3β, Bcl-2 was unstable in an ubiquitination-dependent manner in both basal- and paclitaxeltreated cells. Furthermore, we demonstrate that GSK-3β-mediated regulation of Bcl-2 influences cytochrome C release and mitochondrial membrane potential. Taken together, our data suggest that GSK-3β-dependent regulation of Bcl-2 is crucial for mitochondria-dependent cell death in paclitaxel-mediated breast cancer therapy.