SIRT3-SOD2-ROS pathway is involved in Linalool-induced glioma cell apoptotic death
AbstractGlioma is the most prevalent type of adult primary brain tumor and chemotherapy of glioma was limited by drug-resistance. Linalool is an acyclic monoterpene alcohol possessing various pharmacological activities. The present study was conducted to evaluate the effect of Linalool on glioma cell growth. The effect of Linalool on U87-MG cells was investigated and the results showed that Linalool significantly reduced cell viability in U87-MG cells in a concentration and time-dependent manner. In addition, exposure of cells to Linalool resulted in concentration-dependent increase of TUNEL-stained cells, indicating the occurrence of apoptotic cell death. Linalool decreased mitochondrial oxygen consumption rate, increased the expression of Bax and Bcl-2, reduced the expression of Bcl-2 and Bcl-xl, and increased the activities of caspase 3 and caspase 9, leading to increase of apoptosis. Linalool resulted in a concentration-dependent decrease of SOD activity but had no significant effect on the mRNA and protein expression of SOD2. Moreover, Linalool resulted in a significant increase of acetylated SOD2. The mRNA and protein expression of SIRT3 was significantly inhibited by Linalool. Immunoblot analysis showed that there were protein/protein interaction of SOD2 and SIRT3 in control U87-MG cells. Linalool treatment significantly decreased the interaction of SOD2 and SIRT3. Overexpression of SIRT3 significantly inhibited Linalool-induced increase of mitochondrial ROS level, apoptotic cell death and decrease of cell viability. In summary, we found that Linalool exhibited inhibitory effect on glioma cells through regulation of SIRT3-SOD2-ROS signaling.
Adamson DC, Rasheed BA, McLendon RE and Bigner DD: Central nervous system. Cancer biomarkers : section A of Disease markers 9: 193-210, 2010.
Ding Z, Liu Y, Yao L, et al.: Spy1 induces de-ubiquitinating of RIP1 arrest and confers glioblastoma's resistance to tumor necrosis factor (TNF-alpha)-induced apoptosis through suppressing the association of CLIPR-59 and CYLD. Cell cycle (Georgetown, Tex.) 14: 2149-2159, 2015.
Vigneswaran K, Neill S and Hadjipanayis CG: Beyond the World Health Organization grading of infiltrating glioma: advances in the molecular genetics of glioma classification. Annals of translational medicine 3: 95, 2015.
Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta neuropathologica 114: 97-109, 2007.
Fuller GN and Scheithauer BW: The 2007 Revised World Health Organization (WHO) Classification of Tumours of the Central Nervous System: newly codified entities. Brain pathology (Zurich, Switzerland) 17: 304-307, 2007.
Nakazato Y: [The 4th Edition of WHO Classification of Tumours of the Central Nervous System published in 2007]. No shinkei geka. Neurological surgery 36: 473-491, 2008.
Friedman HS, Kerby T and Calvert H: Temozolomide and treatment of malignant glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 6: 2585-2597, 2000.
Ostrom QT, Gittleman H, Farah P, et al.: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro-oncology 15 Suppl 2: ii1-56, 2013.
Goodenberger ML and Jenkins RB: Genetics of adult glioma. Cancer genetics 205: 613-621, 2012.
Bondy ML, Scheurer ME, Malmer B, et al.: Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113: 1953-1968, 2008.
Omuro A and DeAngelis LM: Glioblastoma and other malignant glioma: a clinical review. Jama 310: 1842-1850, 2013.
Ohgaki H: Epidemiology of brain tumors. Methods in molecular biology (Clifton, N.J.) 472: 323-342, 2009.
Grossman SA, Ye X, Piantadosi S, et al.: Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clinical cancer research : an official journal of the American Association for Cancer Research 16: 2443-2449, 2010.
Stupp R, Hegi ME, Mason WP, et al.: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet. Oncology 10: 459-466, 2009.
Weller M, Cloughesy T, Perry JR and Wick W: Standards of care for treatment of recurrent glioblastoma--are we there yet? Neuro-oncology 15: 4-27, 2013.
Letizia CS, Cocchiara J, Lalko J and Api AM: Fragrance material review on linalool. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 41: 943-964, 2003.
Batista PA, Werner MF, Oliveira EC, et al.: The antinociceptive effect of (-)-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice. The journal of pain : official journal of the American Pain Society 11: 1222-1229, 2010.
Berliocchi L, Russo R, Levato A, et al.: (-)-Linalool attenuates allodynia in neuropathic pain induced by spinal nerve ligation in c57/bl6 mice. International review of neurobiology 85: 221-235, 2009.
Peana AT, D'Aquila PS, Panin F, Serra G, Pippia P and Moretti MD: Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils. Phytomedicine : international journal of phytotherapy and phytopharmacology 9: 721-726, 2002.
do Socorro SRMS, Mendonca-Filho RR, Bizzo HR, et al.: Antileishmanial activity of a linalool-rich essential oil from Croton cajucara. Antimicrobial agents and chemotherapy 47: 1895-1901, 2003.
Peana AT, D'Aquila PS, Chessa ML, Moretti MD, Serra G and Pippia P: (-)-Linalool produces antinociception in two experimental models of pain. European journal of pharmacology 460: 37-41, 2003.
Paik SY, Koh KH, Beak SM, Paek SH and Kim JA: The essential oils from Zanthoxylum schinifolium pericarp induce apoptosis of HepG2 human hepatoma cells through increased production of reactive oxygen species. Biological & pharmaceutical bulletin 28: 802-807, 2005.
Jana S, Patra K, Sarkar S, et al.: Antitumorigenic potential of linalool is accompanied by modulation of oxidative stress: an in vivo study in sarcoma-180 solid tumor model. Nutrition and cancer 66: 835-848, 2014.
Russo R, Ciociaro A, Berliocchi L, et al.: Implication of limonene and linalyl acetate in cytotoxicity induced by bergamot essential oil in human neuroblastoma cells. Fitoterapia 89: 48-57, 2013.
Crowell PL: Prevention and therapy of cancer by dietary monoterpenes. The Journal of nutrition 129: 775s-778s, 1999.
Bardon S, Picard K and Martel P: Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 gene expression in human breast cancer cell lines. Nutrition and cancer 32: 1-7, 1998.
Youle RJ and Strasser A: The BCL-2 protein family: opposing activities that mediate cell death. Nature reviews. Molecular cell biology 9: 47-59, 2008.
Danial NN: BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clinical cancer research : an official journal of the American Association for Cancer Research 13: 7254-7263, 2007.
Adams JM and Cory S: The Bcl-2 protein family: arbiters of cell survival. Science (New York, N.Y.) 281: 1322-1326, 1998.
Lindsten T, Ross AJ, King A, et al.: The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Molecular cell 6: 1389-1399, 2000.
Kuwana T, Mackey MR, Perkins G, et al.: Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111: 331-342, 2002.
Stennicke HR, Jurgensmeier JM, Shin H, et al.: Pro-caspase-3 is a major physiologic target of caspase-8. The Journal of biological chemistry 273: 27084-27090, 1998.
Salvesen GS: Caspases and apoptosis. Essays in biochemistry 38: 9-19, 2002.
Cerchiara T, Straface SV, Brunelli E, Tripepi S, Gallucci MC and Chidichimo G: Antiproliferative effect of linalool on RPMI 7932 human melanoma cell line: ultrastructural studies. Natural product communications 10: 547-549, 2015.
Chang MY and Shen YL: Linalool exhibits cytotoxic effects by activating antitumor immunity. Molecules (Basel, Switzerland) 19: 6694-6706, 2014.
Chang MY, Shieh DE, Chen CC, Yeh CS and Dong HP: Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs. International journal of molecular sciences 16: 28169-28179, 2015.
Gu Y, Ting Z, Qiu X, et al.: Linalool preferentially induces robust apoptosis of a variety of leukemia cells via upregulating p53 and cyclin-dependent kinase inhibitors. Toxicology 268: 19-24, 2010.
Gupta S, Kass GE, Szegezdi E and Joseph B: The mitochondrial death pathway: a promising therapeutic target in diseases. Journal of cellular and molecular medicine 13: 1004-1033, 2009.
Chen X, Hopke PK and Carter WP: Secondary organic aerosol from ozonolysis of biogenic volatile organic compounds: chamber studies of particle and reactive oxygen species formation. Environmental science & technology 45: 276-282, 2011.
Han HD, Cho YJ, Cho SK, et al.: Linalool-Incorporated Nanoparticles as a Novel Anticancer Agent for Epithelial Ovarian Carcinoma. Molecular cancer therapeutics 15: 618-627, 2016.
Mimica-Dukic N, Bugarin D, Grbovic S, et al.: Essential oil of Myrtus communis L. as a potential antioxidant and antimutagenic agents. Molecules (Basel, Switzerland) 15: 2759-2770, 2010.
Usta J, Kreydiyyeh S, Knio K, Barnabe P, Bou-Moughlabay Y and Dagher S: Linalool decreases HepG2 viability by inhibiting mitochondrial complexes I and II, increasing reactive oxygen species and decreasing ATP and GSH levels. Chemico-biological interactions 180: 39-46, 2009.
Tao NN, Zhou HZ, Tang H, et al.: Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway. Oncotarget2016.
Pi H, Xu S, Reiter RJ, et al.: SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 11: 1037-1051, 2015.
Acta Biochimica Polonica is an open access quarterly and publishes four issues a year. All contents are distributed under the Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) license. Everybody may use the content following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made, ShareAlike — If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original. There are no additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Copyright for all published papers © stays with the authors.
Copyright for the journal: © Polish Biochemical Society.