Targeting Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase 2 by Curcumin Induces ER Stress-Associated Apoptosis for Treating Human Liposarcoma

Abstract

Human liposarcoma is the most common soft tissue sarcoma. There is no effective therapy so far except for surgery. In this study, we report for the first time that curcumin induces endoplasmic reticulum (ER) stress in human liposarcoma cells via interacting with sarcoplasmic/endoplasmic reticulum Ca 2þ -ATPase 2 (SERCA2). Curcumin dose-dependently inhibited the cell survival of human liposarcoma cell line SW872 cells, but did not affect that of human normal adipose-derived cells. Curcumin-mediated ER stress via inhibiting the activity of SERCA2 caused increasing expressions of CHOP and its transcription target death receptor 5 (TRAIL-R2), leading to a caspase-3 and caspase-8 cascade-dependent apoptosis in SW872 cells in vitro and in vivo. Moreover, 70% of human liposarcoma tissues showed an elevated SERCA2 expression compared with normal adipose tissues. Curcumin dose-dependently inhibited the activity of SERCA2, and the interaction of molecular docking and colocalization in ER of curcumin with SERCA2 were further observed. These findings suggest that curcumin may serve as a potent agent for curing human liposarcoma via targeting SERCA2. Mol Cancer Ther; 10(3); 461-71. Ó2011 AACR.

Curcumin Differentially Regulates Endoplasmic Reticulum Stress through Transcriptional Corepressor SMILE (Small Heterodimer Partner-interacting Leucine Zipper Protein)-mediated Inhibition of CREBH (cAMP Responsive Element-binding Protein H)

“…The acceleration of oxidative protein folding by curcumin (10 -50 M) has already been reported (32). Previously, it was reported that curcumin plays an important role in ER stressmediated cellular apoptosis processes, whereby curcumin induces ER stress (35,36). It has also been reported that curcumin (5-10 M) induces ER stress response and protects against oxidative stress in the myogenic C2C12 cell line by increasing levels of the ER chaperon protein, GRP94, which acts as a regulator of calcium homeostasis (36).…”

Involvement of the Ca2+-responsive transactivator in high glucose-induced β-cell apoptosis

“…It has been demonstrated that chronic exposure of b-cells to high glucose resulted in the apoptosis of b-cells (Donath et al 1999, Kim et al 2005, Lablanche et al 2011. In addition, lipotoxicity and ER stress were also the important factors leading to b-cell apoptosis (Choi et al 2007, Sano et al 2009, Wang et al 2011. However, the mechanisms for this factor-associated apoptosis of b-cells have remained elusive.…”

“…Under the present experimental conditions, this ratio was clearly altered. Finally, as recent studies have revealed that Ca 2C was also involved in lipotoxicity-and ER stress-induced b-cell apoptosis (Choi et al 2007, Sano et al 2009, Wang et al 2011, the potential role of CREST in these processes was also investigated. Interestingly, ER stress and FFA mimicked the high glucose effects in regard to CREST upregulation and apoptosis induction in cultured b-cells.…”

“…In addition, the mechanisms of CREST-mediated apoptosis upon such cultured cells were analyzed. Moreover, given that some recent studies found that Ca 2C was also involved in lipotoxicity-and ER stress-induced apoptosis in pancreatic b-cells (Choi et al 2007, Sano et al 2009, Wang et al 2011, the role of CREST in mediating these processes was also investigated.…”

Canonical Transient Receptor Potential Channel 2 (TRPC2) as a Major Regulator of Calcium Homeostasis in Rat Thyroid FRTL-5 Cells

“…The samples were centrifuged at 10,000 rpm for 15 min at 4°C. The supernatant was discarded, and the sediment was dissolved in HBSS buffer and sonicated, and SERCA activity was measured according to the manufacturer's instructions (Nanjing Jiancheng Bioengineering Inst., Nanjing City, China) (30). The kit measures inorganic phosphorus (P i ) content produced from ATPase activity in the samples when ATP is broken down to ADP and P i .…”