Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración

Antonela Sofía  Asad; Camila Florencia   Zuccato; Alejandro Javier  Nicola Candia; María Florencia  Gottardo; Mariela Alejandra Moreno Ayala; María Susana Theas; Adriana  Seilicovich; Marianela Candolfi

doi:10.22490/24629448.3630

Vol. 17 Núm. 32 (2019)

Publicado

2019-11-15

PDF

Métricas

Cargando métricas ...

Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración

DOI: https://doi.org/10.22490/24629448.3630

Sección

Artículo de Revisión

Antonela Sofía Asad

Camila Florencia Zuccato

Alejandro Javier Nicola Candia

María Florencia Gottardo

Mariela Alejandra Moreno Ayala

María Susana Theas

Adriana Seilicovich

Marianela Candolfi

La humanina es un péptido derivado de la mitocondria con efectos protectores robustos contra una gran variedad de estímulos citotóxicos en diversos tipos celulares. Esto la convierte en un blanco terapéutico interesante para muchas enfermedades, como el cáncer y enfermedades neurodegenerativas, entre otras. Además, este péptido podría utilizarse como un biomarcador en estas enfermedades. Durante la última década, han sido desarrollados análogos y péptido-miméticos de la humanina que muestran resultados prometedores en modelos preclínicos. A su vez, también se está explorando el potencial terapéutico de vectores de terapia génica que puedan sobreexpresar o silenciar la humanina endógena.
Varios puntos importantes a considerar antes de trasladar estas estrategias terapéuticas a la clínica son su posible papel en la progresión del cáncer y la eventual generación de quimiorresistencia. Todos estos temas serán abordados en este artículo de revisión.

Humanina, péptido mitocondrial, cáncer, enfermedades neurodegenerativas

Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, et al. A Rescue Factor Abolishing Neuronal Cell Death by a Wide Spectrum of Familial Alzheimer’s Disease Genes and Abeta. Proc Natl Acad Sci U S A. 2001; 98(11): p. 6336-41.

Lee C, Yen K, and Cohen P. Humanin: A Harbinger of Mitochondrial-Derived Peptides? Trends in endocrinology and metabolism: TEM. 2013; 24(5): p. 222-8.

Yamagishi Y, Hashimoto Y, Niikura T, and Nishimoto I. Identification of Essential Amino Acids in Humanin, a Neuroprotective Factor against Alzheimer’s Disease-Relevant Insults. Peptides. 2003; 24(4): p. 585-95.

Charununtakorn ST, Shinlapawittayatorn K, Chattipakorn SC, and Chattipakorn N. Potential Roles of Humanin on Apoptosis in the Heart. Cardiovascular Therapeutics. 2016; 34(2): p. 107-14.

Muzumdar RH, Huffman DM, Calvert JW, Jha S, Weinberg Y, Cui L, et al. Acute Humanin Therapy Attenuates Myocardial Ischemia and Reperfusion Injury in Mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010; 30(10): p. 1940-8.

Tajima H, Niikura T, Hashimoto Y, Ito Y, Kita Y, Terashita K, et al. Evidence for in Vivo Production of Humanin Peptide, a Neuroprotective Factor against Alzheimer’s Disease-Related Insults. Neurosci Lett. 2002; 324(3): p. 227-31.

Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, et al. Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer’s Disease-Relevant Insults. J Neurosci. 2001; 21(23): p. 9235-45.

Hashimoto Y, Kurita M, Aiso S, Nishimoto I, and Matsuoka M. Humanin Inhibits Neuronal Cell Death by Interacting with a Cytokine Receptor Complex or Complexes Involving Cntf Receptor Alpha/Wsx-1/Gp130. Mol Biol Cell. 2009; 20(12):
p. 2864-73.

Bodzioch M, Lapicka-Bodzioch K, Zapala B, Kamysz W, Kiec-Wilk B, and Dembinska-Kiec A. Evidence for Potential Functionality of Nuclearly- Encoded Humanin Isoforms. Genomics. 2009; 94(4): p. 247-56.

Terashita K, Hashimoto Y, Niikura T, Tajima H, Yamagishi Y, Ishizaka M, et al. Two Serine Residues Distinctly Regulate the Rescue Function of Humanin, an Inhibiting Factor of Alzheimer’s Disease-Related Neurotoxicity: Functional Potentiation by
Isomerization and Dimerization. Journal of Neurochemistry. 2003; 85(6): p. 1521-38.

Benaki D, Zikos C, Evangelou A, Livaniou E, Vlassi M, Mikros E, et al. Solution Structure of Humanin, a Peptide against Alzheimer’s Disease-Related Neurotoxicity. Biochem Biophys Res Commun. 2005; 329(1): p. 152-60.

Cobb LJ, Lee C, Xiao J, Yen K, Wong RG, Nakamura HK, et al. Naturally Occurring Mitochondrial-Derived Peptides Are Age-Dependent Regulators of Apoptosis, Insulin Sensitivity, and Inflammatory Markers. Aging. 2016; 8(4): p. 796-809.

Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, et al. Humanin Is Expressed in Human Vascular Walls and Has a Cytoprotective Effect against Oxidized Ldl-Induced Oxidative Stress. Cardiovascular Research. 2010; 88(2): p.
360-6.

Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S, et al. Humanin: A Novel Central Regulator of Peripheral Insulin Action. PloS one. 2009; 4(7): p. e6334.

Conte M, Ostan R, Fabbri C, Santoro A, Guidarelli G, Vitale G, et al. Human Aging and Longevity Are Characterized by High Levels of Mitokines. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2018; 74(5): p. 600-7.

Gong Z, Tas E, and Muzumdar R. Humanin and Age-Related Diseases: A New Link? Frontiers in Endocrinology. 2014; 5: p. 210.

Rossini L, Hashimoto Y, Suzuki H, Kurita M, Gianfriddo M, Scali C, et al. Vstm2l Is a Novel Secreted Antagonist of the Neuroprotective Peptide Humanin. FASEB Journal : Official Publication of the Federation of American Societies for Experimental
Biology. 2011; 25(6): p. 1983-2000.

Xiao J, Kim SJ, Cohen P, and Yen K. Humanin: Functional Interfaces with Igf-I. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2016; 29: p. 21-27.

Niikura T, Hashimoto Y, Tajima H, Ishizaka M, Yamagishi Y, Kawasumi M, et al. A Tripartite Motif Protein Trim11 Binds and Destabilizes Humanin, a Neuroprotective Peptide against Alzheimer’s Disease- Relevant Insults. The European Journal of Neuroscience. 2003; 17(6): p. 1150-8.

Lee C, Wan J, Miyazaki B, Fang Y, Guevara-Aguirre J, Yen K, et al. Igf-I Regulates the Age-Dependent Signaling Peptide Humanin. Aging Cell. 2014; 13(5): p. 958-61.

Gottardo MF, Jaita G, Magri ML, Zarate S, Moreno Ayala M, Ferraris J, et al. Antiapoptotic Factor Humanin Is Expressed in Normal and Tumoral Pituitary Cells and Protects Them from Tnf-Alpha-Induced Apoptosis. PloS one. 2014; 9(10): p. e111548.

Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, et al. Humanin Peptide Suppresses Apoptosis by Interfering with Bax Activation. Nature. 2003; 423(6938): p. 456-61.

Jia Y, Lue YH, Swerdloff R, Lee KW, Cobb LJ, Cohen P, et al. The Cytoprotective Peptide Humanin Is Induced and Neutralizes Bax after Pro-Apoptotic Stress in the Rat Testis. Andrology. 2013; 1(4): p. 651-9.

Gottardo MF, Pidre ML, Zuccato C, Asad AS, Imsen M, Jaita G, et al. Baculovirus-Based Gene Silencing of Humanin for the Treatment of Pituitary Tumors. Apoptosis : An International Journal on Programmed Cell Death. 2018; 23(2): p. 143-151.

Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC, and Reed JC. Humanin Binds and Nullifies Bid Activity by Blocking Its Activation of Bax and Bak. The Journal of Biological Chemistry. 2005; 280(16): p. 15815-24.

Ma ZW and Liu DX. Humanin Decreases Mitochondrial Membrane Permeability by Inhibiting the Membrane Association and Oligomerization of Bax and Bid Proteins. Acta Pharmacologica Sinica. 2018; 39(6): p. 1012-1021.

Xie Y, Liu ZH, Li XY, Zhou YD, Xu X, Hu LF, et al. Protection Effect of [Gly14]-Humanin from Apoptosis Induced by High Glucose in Human Umbilical Vein Endothelial Cells. Diabetes Research and Clinical Practice. 2014; 106(3): p. 560-6.

Gottardo MF, Moreno Ayala M, Ferraris J, Zarate S, Pisera D, Candolfi M, et al. Humanin Inhibits Apoptosis in Pituitary Tumor Cells through Several Signaling Pathways Including Nf-Kappab Activation. Journal of Cell Communication and Signaling.
2017; 11(4): p. 329-340.

Sreekumar PG, Ishikawa K, Spee C, Mehta HH, Wan J, Yen K, et al. The Mitochondrial-Derived Peptide Humanin Protects Rpe Cells from Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Investigative Ophthalmology & Visual Science.
2016; 57(3): p. 1238-53.

Matsuoka M and Hashimoto Y. Humanin and the Receptors for Humanin. Molecular Neurobiology. 2010; 41(1): p. 22-8.

Hashimoto Y, Kurita M, and Matsuoka M. Identification of Soluble Wsx-1 Not as a Dominant-Negative but as an Alternative Functional Subunit of a Receptor for an Anti-Alzheimer’s Disease Rescue Factor Humanin. Biochemical and Biophysical Research Communications. 2009; 389(1): p. 95-9.

Hoang PT, Park P, Cobb LJ, Paharkova-Vatchkova V, Hakimi M, Cohen P, et al. The Neurosurvival Factor Humanin Inhibits Beta-Cell Apoptosis Via Signal Transducer and Activator of Transcription 3 Activation and Delays and Ameliorates Diabetes in Nonobese Diabetic Mice. Metabolism: Clinical and Experimental. 2010; 59(3): p. 343-9.

Hashimoto Y, Suzuki H, Aiso S, Niikura T, Nishimoto I, and Matsuoka M. Involvement of Tyrosine Kinases and Stat3 in Humanin-Mediated Neuroprotection. Life Sciences. 2005; 77(24): p. 3092-104.

Kim SJ, Guerrero N, Wassef G, Xiao J, Mehta HH, Cohen P, et al. The Mitochondrial-Derived Peptide Humanin Activates the Erk1/2, Akt, and Stat3 Signaling Pathways and Has Age-Dependent Signaling Differences in the Hippocampus. Oncotarget. 2016; 7(30): p. 46899-46912.

Ying G, Iribarren P, Zhou Y, Gong W, Zhang N, Yu ZX, et al. Humanin, a Newly Identified Neuroprotective Factor, Uses the G Protein-Coupled Formylpeptide Receptor-Like-1 as a Functional Receptor. J Immunol. 2004; 172(11): p. 7078-85.

Hashimoto Y, Takeshita Y, Naito M, Uchino H, and Matsuoka M. Apollon/Bruce Is Upregulated by Humanin. Molecular and cellular biochemistry. 2014; 397(1-2): p. 147-55.

Gong Z and Tasset I. Humanin Enhances the Cellular Response to Stress by Activation of Chaperone- Mediated Autophagy. Oncotarget. 2018; 9(13): p. 10832-10833.

Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s Disease. Lancet. 2016; 388(10043): p. 505-17.

Hashimoto Y, Ito Y, Niikura T, Shao Z, Hata M, Oyama F, et al. Mechanisms of Neuroprotection by a Novel Rescue Factor Humanin from Swedish Mutant Amyloid Precursor Protein. Biochemical and Biophysical Research Communications. 2001;
283(2): p. 460-8.

Mamiya T and Ukai M. [Gly(14)]-Humanin Improved the Learning and Memory Impairment Induced by Scopolamine in Vivo. Br J Pharmacol. 2001; 134(8): p. 1597-9.

Niikura T, Sidahmed E, Hirata-Fukae C, Aisen PS, and Matsuoka Y. A Humanin Derivative Reduces Amyloid Beta Accumulation and Ameliorates Memory Deficit in Triple Transgenic Mice. PloS one. 2011; 6(1): p. e16259.

Zhang W, Li Z, Hao J, Zhang Z, Liu L, Mao N, et al. S14g-Humanin Improves Cognitive Deficits and Reduces Amyloid Pathology in the Middle-Aged Appswe/Ps1de9 Mice. Pharmacol Biochem Behav. 2012; 100(3): p. 361-9.

Zhao ST, Zhao L, and Li JH. Neuroprotective Peptide Humanin Inhibits Inflammatory Response in Astrocytes Induced by Lipopolysaccharide. Neurochemical Research. 2013; 38(3): p. 581-8.

Peng T, Wan W, Wang J, Liu Y, Fu Z, Ma X, et al. The Neurovascular Protective Effect of S14g-Humanin in a Murine Mcao Model and Brain Endothelial Cells. IUBMB Life. 2018; 70(7): p. 691-699.

Yuan L, Liu XJ, Han WN, Li QS, Wang ZJ, Wu MN, et al. [Gly14]-Humanin Protects against AmyloidBeta Peptide-Induced Impairment of Spatial Learning and Memory in Rats. Neuroscience Bulletin. 2016; 32(4): p. 374-82.

Chiba T, Yamada M, Hashimoto Y, Sato M, Sasabe J, Kita Y, et al. Development of a Femtomolar-Acting Humanin Derivative Named Colivelin by Attaching Activity-Dependent Neurotrophic Factor to Its N Terminus: Characterization of Colivelin-Mediated Neuroprotection against Alzheimer’s Disease- Relevant Insults in Vitro and in Vivo. J Neurosci. 2005; 25(44): p. 10252-61.

Yin R, Yin K, Guo Z, Zhang Z, Chen L, Cao L, et al. Protective Effects of Colivelin against Alzheimer’s Disease in a Pdapp Mouse Model. Cell Physiol Biochem. 2016; 38(3): p. 1138-46.

Cui AL, Zhang YH, Li JZ, Song T, Liu XM, Wang H, et al. Humanin Rescues Cultured Rat Cortical Neurons from Nmda-Induced Toxicity through the Alleviation of Mitochondrial Dysfunction. Drug Design, Development and Therapy. 2017; 11: p.
1243-1253.

Alam MP, Bilousova T, Spilman P, Vadivel K, BaiD, Elias CJ, et al. A Small Molecule Mimetic of the Humanin Peptide as a Candidate for Modulating Nmda-Induced Neurotoxicity. ACS Chemical Neuroscience. 2018; 9(3): p. 462-468.

Gao GS, Li Y, Zhai H, Bi JW, Zhang FS, Zhang XY, et al. Humanin Analogue, S14g-Humanin, Has Neuroprotective Effects against Oxygen Glucose Deprivation/Reoxygenation by Reactivating Jak2/ Stat3 Signaling through the Pi3k/Akt Pathway. Experimental and Therapeutic Medicine. 2017; 14(4): p. 3926-3934.

Ambati J and Fowler BJ. Mechanisms of Age-Related Macular Degeneration. Neuron. 2012; 75(1): p. 26-39.

Garzón P, Sandra Johanna et al. Características cognitivas y oculares en enfermedad de Alzheimer. Nova, [S.l.], v. 16, n. 29, p. 101 - 114, sep. 2018. ISSN 2462-9448. Disponible en: <http://hemeroteca.unad.edu.co/index.php/nova/article/view/2693>. Fecha de acceso: 14 mar. 2019 doi:https://doi.org/10.22490/24629448.2693.

Matsunaga D, Sreekumar PG, Ishikawa K, Terasaki H, Barron E, Cohen P, et al. Humanin Protects Rpe Cells from Endoplasmic Reticulum Stress-Induced Apoptosis by Upregulation of Mitochondrial Glutathione. PLoS One. 2016; 11(10): p. e0165150.

Maximov V, Martynenko A, Hunsmann G, and Tarantul V. Mitochondrial 16s Rrna Gene Encodes a Functional Peptide, a Potential Drug for Alzheimer’s Disease and Target for Cancer Therapy. Medical Hypotheses. 2002; 59(6): p. 670-3.

Mottaghi-Dastjerdi N, Soltany-Rezaee-Rad M, Sepehrizadeh Z, Roshandel G, Ebrahimifard F, and Setayesh N. Genome Expression Analysis by Suppression Subtractive Hybridization Identified Overexpression of Humanin, a Target Gene in Gastric
Cancer Chemoresistance. Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2014; 22(1): p. 14.

Omar NN, Tash RF, Shoukry Y, and ElSaeed KO. Breaking the Ritual Metabolic Cycle in Order to Save Acetyl Coa: A Potential Role for Mitochondrial Humanin in T2 Bladder Cancer Aggressiveness. Journal of the Egyptian National Cancer Institute.
2017; 29(2): p. 69-76.

Surampudi P, Chang I, Lue Y, Doumit T, Jia Y, Atienza V, et al. Humanin Protects against Chemotherapy- Induced Stage-Specific Male Germ Cell Apoptosis in Rats. Andrology. 2015; 3(3): p. 582- 589.

Jia Y, Ohanyan A, Lue YH, Swerdloff RS, Liu PY, Cohen P, et al. The Effects of Humanin and Its Analogues on Male Germ Cell Apoptosis Induced by Chemotherapeutic Drugs. Apoptosis : An International Journal on Programmed Cell Death. 2015;
20(4): p. 551-61.

Eriksson E, Wickstrom M, Perup LS, Johnsen JI, Eksborg S, Kogner P, et al. Protective Role of Humanin on Bortezomib-Induced Bone Growth Impairment in Anticancer Treatment. Journal of the National Cancer Institute. 2014; 106(3): p. djt459.

Cohen P. New Role for the Mitochondrial Peptide Humanin: Protective Agent against Chemotherapy- Induced Side Effects. Journal of the National Cancer Institute. 2014; 106(3): p. dju006.

Zuccato C, Moreno Ayala M, Gottardo M, Pidre M, Asad A, Nicola Candia A, et al. Role of Mitochondrial Peptide Humanin in the Response of Experimental Breast Cancer to Chemotherapy. Proceedings of the American Association for Cancer
Research Annual Meeting. Cancer Research. 2018; 78(12 (Suppl)): p. 1951.

Gray GK, McFarland BC, Nozell SE, and Benveniste EN. Nf-Kappab and Stat3 in Glioblastoma: Therapeutic Targets Coming of Age. Expert Review of Neurotherapeutics. 2014; 14(11): p. 1293-306.

Elizalde PV, Cordo Russo RI, Chervo MF, and Schillaci R. Erbb-2 Nuclear Function in Breast Cancer Growth, Metastasis and Resistance to Therapy. Endocrine-related cancer. 2016; 23(12): p. T243-T257.

Banerjee K and Resat H. Constitutive Activation of Stat3 in Breast Cancer Cells: A Review. International Journal of Cancer. 2016; 138(11): p. 2570-8.

Li S, Tian J, Zhang H, Zhou S, Wang X, Zhang L, et al. Down-Regulating Il-6/Gp130 Targets Improved the Anti-Tumor Effects of 5-Fluorouracil in Colon Cancer. Apoptosis : An International Journal on Programmed Cell Death. 2018; 23(5-6): p. 356-
374.

Xiao J, Howard L, Wan J, Wiggins E, Vidal A, Cohen P, et al. Low Circulating Levels of the Mitochondrial- Peptide Hormone Shlp2: Novel Biomarker for Prostate Cancer Risk. Oncotarget. 2017; 8(55): p. 94900-94909.

Kim SJ, Mehta HH, Wan J, Kuehnemann C, Chen J, Hu JF, et al. Mitochondrial Peptides Modulate Mitochondrial Function During Cellular Senescence. Aging. 2018; 10(6): p. 1239-1256.

Schosserer M, Grillari J, and Breitenbach M. The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy. Frontiers in Oncology. 2017; 7: p. 278.

Lasry A and Ben-Neriah Y. Senescence-Associated Inflammatory Responses: Aging and Cancer Perspectives. Trends in Immunology. 2015; 36(4): p. 217-28.

Campisi J, Andersen JK, Kapahi P, and Melov S. Cellular Senescence: A Link between Cancer and Age-Related Degenerative Disease? Seminars in Cancer Biology. 2011; 21(6): p. 354-9.

Freund A, Orjalo AV, Desprez PY, and Campisi J. Inflammatory Networks During Cellular Senescence: Causes and Consequences. Trends in Molecular Medicine. 2010; 16(5): p. 238-46.

Chin YP, Keni J, Wan J, Mehta H, Anene F, Jia Y, et al. Pharmacokinetics and Tissue Distribution of Humanin and Its Analogues in Male Rodents. Endocrinology. 2013; 154(10): p. 3739-44.

Sari Y, Chiba T, Yamada M, Rebec GV, and Aiso S. A Novel Peptide, Colivelin, Prevents Alcohol-Induced Apoptosis in Fetal Brain of C57bl/6 Mice: Signaling Pathway Investigations. Neuroscience. 2009; 164(4): p. 1653-64.

Lalatsa A, Schatzlein AG, and Uchegbu IF. Strategies to Deliver Peptide Drugs to the Brain. Mol Pharm. 2014; 11(4): p. 1081-93.

Yamada M, Chiba T, Sasabe J, Terashita K, Aiso S, and Matsuoka M. Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer’s Disease. Neuropsychopharmacology. 2008; 33(8): p. 2020-32.

Wu H, Li J, Zhang Q, Yan X, Guo L, Gao X, et al. A Novel Small Odorranalectin-Bearing Cubosomes: Preparation, Brain Delivery and Pharmacodynamic Study on Amyloid-Beta(2)(5)(-)(3)(5)-Treated Rats Following Intranasal Administration. Eur J Pharm Biopharm. 2012; 80(2): p. 368-78.

Logan IS. Pseudogenization of the Humanin Gene Is Common in the Mitochondrial DNA of Many Vertebrates. Zoological Research. 2017; 38(4): p. 198-202.

Asad, A. S., Zuccato, C. F. ., Nicola Candia, A. J. ., Gottardo, M. F. ., Moreno Ayala, M. A., Theas, M. S., Seilicovich, A. ., & Candolfi, M. (2019). Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración. Nova, 17(32), 9-24. https://doi.org/10.22490/24629448.3630

Descargar cita

Publicado

Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración

Declaración de privacidad.

Palabras clave