Capsaicin induces apoptosis in PC12 cells through ER stress

Capsaicin, the pungent agent in chili peppers, has been shown to act as a tumor-suppressor in cancer. In our previous study, capsaicin was shown to induce apoptosis in the rat pheochromocytoma cell line (PC12 cells). Thus, the aim of the present study was to determine the potential mechanism by which capsaicin induces apoptosis. We treated PC12 cells with 50, 100 and 500 μM capsaicin and measured the reticular calcium content and expression of the reticular calcium transport systems. These results were correlated with endoplasmic reticulum (ER) stress markers CHOP, ATF4 and X-box binding protein 1 (XBP1), as well as with apoptosis induction. We observed that capsaicin decreased reticular calcium in a concentration-dependent manner. Simultaneously, expression levels of the sarco/endoplasmic reticulum pump and ryanodin receptor of type 2 were modified. These changes were accompanied by increased ER stress, as documented by increased stress markers. Thus, from these results we propose that in PC12 cells capsaicin induces apoptosis through increased ER stress.

[1]  J. Sedlák,et al.  Sulphide signalling potentiates apoptosis through the up‐regulation of IP3 receptor types 1 and 2 , 2013, Acta physiologica.

[2]  S. Sekaran,et al.  Phyllanthus Suppresses Prostate Cancer Cell, PC-3, Proliferation and Induces Apoptosis through Multiple Signalling Pathways (MAPKs, PI3K/Akt, NFκB, and Hypoxia) , 2013, Evidence-based complementary and alternative medicine : eCAM.

[3]  S. Takeda,et al.  Capsaicin mimics mechanical load-induced intracellular signaling events , 2013, Channels.

[4]  C. Romestaing,et al.  Characterization of Functional TRPV1 Channels in the Sarcoplasmic Reticulum of Mouse Skeletal Muscle , 2013, PloS one.

[5]  L. Neckers,et al.  Targeting Heat Shock Protein 90 for the Treatment of Malignant Pheochromocytoma , 2013, PloS one.

[6]  H. Shimano,et al.  Inhibition of autophagy enhances sunitinib-induced cytotoxicity in rat pheochromocytoma PC12 cells. , 2013, Journal of pharmacological sciences.

[7]  Jah-yao Liu,et al.  Triptolide Transcriptionally Represses HER2 in Ovarian Cancer Cells by Targeting NF-κB , 2012, Evidence-based complementary and alternative medicine : eCAM.

[8]  K. Pacak,et al.  NF‐κB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model , 2012, International journal of cancer.

[9]  H. Shimano,et al.  Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD. , 2012, American journal of physiology. Endocrinology and metabolism.

[10]  Tony Taldone,et al.  Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. , 2012, Biochimica et biophysica acta.

[11]  G. Santoni,et al.  Antioncogenic Effects of Transient Receptor Potential Vanilloid 1 in the Progression of Transitional Urothelial Cancer of Human Bladder , 2012, ISRN urology.

[12]  J. Varner,et al.  A review of the mammalian unfolded protein response , 2011, Biotechnology and bioengineering.

[13]  D. Galson,et al.  Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells. , 2011, Experimental hematology.

[14]  G. Santoni,et al.  Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells. , 2011, Carcinogenesis.

[15]  M. White,et al.  Stressed to death: targeting endoplasmic reticulum stress response induced apoptosis in gliomas. , 2011, Current pharmaceutical design.

[16]  Ó. Teijido,et al.  Upregulation of Bcl2 inhibits apoptosis‐driven BAX insertion but favors BAX relocalization in mitochondria , 2010, FEBS letters.

[17]  C. Hetz,et al.  HSP72 Protects Cells from ER Stress-induced Apoptosis via Enhancement of IRE1α-XBP1 Signaling through a Physical Interaction , 2010, PLoS biology.

[18]  R. Clarke,et al.  The role of X-box binding protein-1 in tumorigenicity. , 2009, Drug news & perspectives.

[19]  S. Fulda Tumor resistance to apoptosis , 2009, International journal of cancer.

[20]  M. A. Lasunción,et al.  Induction of the endoplasmic reticulum stress protein GADD153/CHOP by capsaicin in prostate PC-3 cells: a microarray study. , 2008, Biochemical and biophysical research communications.

[21]  F. Grespi,et al.  Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? , 2008, Cell Death and Differentiation.

[22]  C. Hetz ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage. , 2007, Antioxidants & redox signaling.

[23]  H. Valdivia One gene, many proteins: alternative splicing of the ryanodine receptor gene adds novel functions to an already complex channel protein. , 2007, Circulation research.

[24]  J. Jakubikova,et al.  Isothiocyanates induce cell cycle arrest, apoptosis and mitochondrial potential depolarization in HL-60 and multidrug-resistant cell lines. , 2005, Anticancer research.

[25]  R. Kaufman,et al.  The mammalian unfolded protein response. , 2003, Annual review of biochemistry.

[26]  L. Hendershot,et al.  The role of the unfolded protein response in tumour development: friend or foe? , 2004, Nature Reviews Cancer.

[27]  H. Yamaguchi,et al.  CHOP Is Involved in Endoplasmic Reticulum Stress-induced Apoptosis by Enhancing DR5 Expression in Human Carcinoma Cells* , 2004, Journal of Biological Chemistry.

[28]  伊藤 圭介 Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress : Implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species , 2004 .

[29]  G. Breithardt,et al.  xIAP Induces Cell-Cycle Arrest and Activates Nuclear Factor-&kgr;B: New Survival Pathways Disabled by Caspase-Mediated Cleavage During Apoptosis of Human Endothelial Cells , 2001, Circulation research.

[30]  G. Dallner,et al.  The effects of inducers of the endoplasmic reticulum, peroxisomes and mitochondria on the amounts and synthesis of ubiquinone in rat liver subcellular membranes. , 1990, Chemico-biological interactions.

[31]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.