Melatonin Promotes Apoptosis of Colorectal Cancer Cells via Superoxide-mediated ER Stress by Inhibiting Cellular Prion Protein Expression

Background/Aim: Melatonin, an endogenously secreted indoleamine hormone that is produced in the pineal gland, is known to possess antitumor effect via various mechanisms including induction of apoptosis and pro-oxidant effects in various cancer cells, including colorectal cancer (CRC). In our study, we hypothesized that melatonin enhances the anticancer effects via suppression of PrPC and PINK1 levels, thereby increasing superoxide production. Materials and Methods: To investigate the antitumor effects of melatonin in CRC cells, assessing its effects on mitochondrial dysfunction, production of superoxide, induction of endoplasmic reticulum stress, and cellular apoptosis were assessed. Results: Melatonin was found to decrease the expression of PrPC and PINK1, and increase superoxide accumulation in the mitochondria. In addition, PrPC-knockdown potentiated the effects of melatonin resulting further in significantly reduced expression of PINK1 and increased superoxide production in CRC. si-PRNP-transfected CRC cells treated with melatonin increased the production of intracellular superoxide and induced endoplasmic reticulum stress associated protein, and apoptosis. Conclusion: Melatonin induces mitochondria-mediated cellular apoptosis in CRC cancer cells via a PrPC-dependent pathway. PrPC knockdown combined with melatonin amplifies the effects of melatonin, suggesting a novel therapeutic strategy in targeting CRC cells.

[1]  J. H. Lee,et al.  Melatonin Promotes Apoptosis of Oxaliplatin-resistant Colorectal Cancer Cells Through Inhibition of Cellular Prion Protein. , 2018, Anticancer research.

[2]  R. Reiter,et al.  Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation , 2018, Journal of pineal research.

[3]  Jian-Hua Luo,et al.  Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway. , 2018, Oncology reports.

[4]  Sung-Hoon Kim,et al.  miR-211 Plays a Critical Role in Cnidium officinale Makino Extract-Induced, ROS/ER Stress-Mediated Apoptosis in U937 and U266 Cells , 2018, International journal of molecular sciences.

[5]  Seema Kumari,et al.  Reactive Oxygen Species: A Key Constituent in Cancer Survival , 2018, Biomarker insights.

[6]  J. H. Lee,et al.  Cellular Prion Protein Enhances Drug Resistance of Colorectal Cancer Cells via Regulation of a Survival Signal Pathway , 2017, Biomolecules & therapeutics.

[7]  Huan-ling Yu,et al.  Elaidic acid induces cell apoptosis through induction of ROS accumulation and endoplasmic reticulum stress in SH-SY5Y cells , 2017, Molecular medicine reports.

[8]  Fred K Tabung,et al.  Dietary Patterns and Colorectal Cancer Risk: a Review of 17 Years of Evidence (2000–2016) , 2017, Current Colorectal Cancer Reports.

[9]  U. Manne,et al.  Prolonged exposure of resveratrol induces reactive superoxide species–independent apoptosis in murine prostate cells , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[10]  Haocai Chang,et al.  Induction of reactive oxygen species: an emerging approach for cancer therapy , 2017, Apoptosis.

[11]  Jane L. Roberts,et al.  Curcumin interacts with sildenafil to kill GI tumor cells via endoplasmic reticulum stress and reactive oxygen/ nitrogen species , 2017, Oncotarget.

[12]  Yue Zhou,et al.  Melatonin for the prevention and treatment of cancer , 2017, Oncotarget.

[13]  A. Ouchida,et al.  The role of mitochondria in metabolism and cell death. , 2017, Biochemical and biophysical research communications.

[14]  J. Bae,et al.  ROS homeostasis and metabolism: a critical liaison for cancer therapy , 2016, Experimental & Molecular Medicine.

[15]  R. Ordoñez,et al.  Melatonin‐induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy , 2016, Journal of pineal research.

[16]  J. H. Lee,et al.  Pivotal Roles of Ginsenoside Rg3 in Tumor Apoptosis Through Regulation of Reactive Oxygen Species. , 2016, Anticancer research.

[17]  S. Yun,et al.  Silencing Prion Protein in HT29 Human Colorectal Cancer Cells Enhances Anticancer Response to Fucoidan. , 2016, Anticancer research.

[18]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[19]  Kyung Jin Lee,et al.  Cellular prion protein regulates invasion and migration of breast cancer cells through MMP-9 activity. , 2016, Biochemical and biophysical research communications.

[20]  M. Kukla,et al.  Effects of ghrelin, leptin and melatonin on the levels of reactive oxygen species, antioxidant enzyme activity and viability of the HCT 116 human colorectal carcinoma cell line. , 2015, Molecular medicine reports.

[21]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[22]  J. Salmerón,et al.  Melatonin reduces endothelin‐1 expression and secretion in colon cancer cells through the inactivation of FoxO‐1 and NF‐κβ , 2014, Journal of pineal research.

[23]  L. Alves,et al.  Ultrastructural aspects of melatonin cytotoxicity on Caco-2 cells in vitro. , 2014, Micron.

[24]  Yonggeun Hong,et al.  Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells , 2014, Journal of pineal research.

[25]  W. Wurst,et al.  The Parkinson’s gene PINK1 regulates cell cycle progression and promotes cancer-associated phenotypes , 2014, Oncogene.

[26]  P. Johnston,et al.  Cancer drug resistance: an evolving paradigm , 2013, Nature Reviews Cancer.

[27]  D. McMillan,et al.  Deprivation and Colorectal Cancer Surgery: Longer-Term Survival Inequalities are Due to Differential Postoperative Mortality Between Socioeconomic Groups , 2013, Annals of Surgical Oncology.

[28]  R. Youle,et al.  Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. , 2012, Cold Spring Harbor perspectives in biology.

[29]  A. M. van der Bliek,et al.  Mitochondrial Fission, Fusion, and Stress , 2012, Science.

[30]  F. Clavel-Chapelon,et al.  Is concordance with World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention related to subsequent risk of cancer? Results from the EPIC study. , 2012, The American journal of clinical nutrition.

[31]  P. Codogno,et al.  Prion protein: From physiology to cancer biology. , 2010, Cancer letters.

[32]  A. Bürkle,et al.  The octarepeat region of prion protein, but not the TM1 domain, is important for the antioxidant effect of prion protein. , 2008, Free radical biology & medicine.

[33]  C. Alonso-González,et al.  Melatonin modulates the cadmium-induced expression of MT-2 and MT-1 metallothioneins in three lines of human tumor cells (MCF-7, MDA-MB-231 and HeLa). , 2008, Toxicology letters.

[34]  M. Álvarez-Martínez,et al.  Physiological role of the cellular prion protein. , 2008, Veterinary research.

[35]  I. Izquierdo,et al.  Physiology of the prion protein. , 2008, Physiological reviews.

[36]  L. Kèlland,et al.  The resurgence of platinum-based cancer chemotherapy , 2007, Nature Reviews Cancer.

[37]  G. Guyatt,et al.  Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta‐analysis , 2005, Journal of pineal research.

[38]  Kiheung Kim,et al.  Ko Kuei Chen: a pioneer of modern pharmacological research in China , 2022, Protein & cell.

[39]  David R. Brown,et al.  Lack of prion protein expression results in a neuronal phenotype sensitive to stress , 2002, Journal of neuroscience research.

[40]  I. Izquierdo,et al.  Imbalance of antioxidant defense in mice lacking cellular prion protein. , 2001, Free radical biology & medicine.

[41]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[42]  H. Kretzschmar,et al.  Prion Protein-Deficient Cells Show Altered Response to Oxidative Stress Due to Decreased SOD-1 Activity , 1997, Experimental Neurology.