Possible Involvement of Both Endoplasmic Reticulum-and Mitochondria-Dependent Pathways in Thapsigargin-Induced Apoptosis in Human Neuroblastoma SH-SY5Y Cells

• Published in: Journal of Pharmacological Sciences Vol. 92; no. 3; pp. 228 - 236
• Main Authors: Kitamura, Yoshihisa, Miyamura, Atsushi, Takata, Kazuyuki, Inden, Masatoshi, Tsuchiya, Daiju, Nakamura, Kumi, Taniguchi, Takashi
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Pharmacological Society 01.07.2003
• Subjects: Apoptosis - drug effects; Apoptosis - physiology; Bcl-2; caspase; Caspases - metabolism; Cell Line, Tumor; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - physiology; endoplasmic reticulum stress; human neuroblastoma SH-SY5Y cell; Humans; Mitochondria - drug effects; Mitochondria - physiology; Neuroblastoma - enzymology; Neuroblastoma - metabolism; Neuroblastoma - pathology; Signal Transduction - drug effects; Signal Transduction - physiology; thapsigargin; Thapsigargin - pharmacology
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.92.228

Recently, it has been shown that endoplasmic reticulum (ER) stress causes apoptosis. However, the mechanism of the ER stress-dependent pathway is not fully understood. In human neuroblastoma SH-SY5Y cells, we detected a caspase-12-like protein that has a molecular mass (approximately 60 kDa) similar to that of mouse caspase-12. Thapsigargin, an inhibitor of ER-associated Ca2+-ATPase, induced the degradation of caspase-12-like protein. In addition, the degradation of caspases-9 and -3, cleavage of poly(ADP-ribose) polymerase, DNA fragmentation, and cell death were also observed. Pretreatment with phorbol-12-myristate-13-acetate, which induces the expression of antiapoptotic Bcl-2, inhibited thapsigargin-induced degradation of caspases-9 and -3, but not caspase-12-like protein degradation. A caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(OCH3)-CH2F, inhibited the degradation of caspase-12-like protein, but not that of caspases-9 and -3. These results suggest that thapsigargin may induce the activation of both ER- and mitochondria-dependent pathways in human SH-SY5Y cells.