Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases

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

doi:10.1080/14728222.2019.1559300

Cited by 38 publications

(30 citation statements)

References 100 publications

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“…Our study shows that HN facilitates tumor progression and chemo-resistance in an experimental model of breast cancer. HN has been shown to protect several cell types from apoptosis, including neurons, endothelial cells, and pancreatic β-cells 10 . In the context of cancer, the role of HN is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…different insults such as serum deprivation, TNF-α treatment and chemotherapy. HN is secreted and binds with cell surface receptors but also acts intracellularly through the interaction with Bax and other proteins of the Bcl-2 family 10 . We have previously reported that the cytoprotective effect of HN in pituitary tumor cells involves STAT3 activation and inhibition of Bax translocation to mitochondria 13 .…”

Section: Discussionmentioning

confidence: 99%

“…HN can also be secreted, exerting autocrine, paracrine and endocrine effects upon interaction with membrane receptors. Two membrane receptors have been identified that bind circulating HN: (i) a trimeric receptor composed by the ciliary neurotrophic factor receptor (CNTFR), the IL27R (WSX-1) and the 130 kDa glycoprotein (gp130), which can trigger the activation of RAS/MAPKs, PI3K, JNK and STAT3; (ii) the formyl peptide receptor-like 1 (FPRL-1 or FPR2), which induces signal-regulated extracellular kinase activation (ERK 1/2) 10 . Activation of these receptors exerts cytoprotection in preclinical models of stroke, diabetes, Alzheimer's disease, among other diseases 14 .…”

mentioning

confidence: 99%

“…HN exerts an antiapoptotic action in many different cell types, such as neurons, endothelial cells, pancreatic beta cells, germ cells and secretory cells of the anterior pituitary gland 10 . The cytoprotective role of HN has been described in different species, including humans, rats and mice [17][18][19][20][21] and this peptide has been proposed to be a therapeutic target in many different diseases, such as Alzheimer's disease, diabetes and atherosclerosis 10 . Although HN has been proposed to be a potential oncopeptide almost 2 decades ago 22 , its role in cancer development and treatment remains poorly understood.…”

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confidence: 99%

“…While the administration of HN and its analogs has shown promising results in preclinical models of degenerative diseases 10 , the controversy on the role of HN in cancer progression and chemoresistance needs to be addressed before translating these therapeutic approaches to the clinical practice. Thus, here we aimed to evaluate the expression and function of HN in human and murine breast tumor cells, as well as its role in tumor progression and chemoresistance in murine models of TNBC.…”

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Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Ayala

Gottardo

Zuccato

et al. 2020

Sci Rep

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Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of Hn analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (tnBc). the meta-analysis of transcriptomic data from the cancer Genome Atlas indicated that Hn and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of Hn in tnBc biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous Hn protected tnBc cells from apoptotic stimuli whereas shRnA-mediated Hn silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer. Breast cancer is the most common cause of death by cancer in women 1. Although new strategies have been developed for the treatment of breast tumors that express hormone receptors and/or human epidermal growth factor receptor 2 (Her2), there are no therapeutic options for patients with triple negative breast cancer (TNBC), for whom chemotherapy/radiotherapy remains the first-line treatment 2,3. Since these tumors frequently develop chemo-resistance 4 , novel therapeutic targets are urgently needed to improve the treatment of TNBC. A cytoprotective mitochondrial-derived peptide, humanin (HN), was discovered in healthy neurons of patients suffering Alzheimer's disease 5. HN was the first small open reading frame (ORF) identified within the mitochondrial DNA, encoded within the 16S rRNA gene (MT-RNR2) 6. HN can be translated both in the mitochondrial matrix or the cytosol, resulting in biologically functional 21 and 24-amino acid peptides, respectively 7. Small ORFs for six other small HN-like peptides (SHLPs) have been detected in the mitochondrial genome, two of which (SHLP2 and SHLP3) exhibit biological activity 8. Thirteen MT-RNR2-like loci that encode for fifteen HN-like peptides were detected in the nuclear genome 9. However, the expression of the mitochondrial gene MT-RNR2 is substantially higher than any nuclear isoform 9. HN regulates the mitochondrial apoptotic pathway by interaction with proteins of the Bcl-2 family 10. Intracellular HN binds to proapoptotic proteins, such as Bax, tBid and BimEL inhibiting the release of cytochrome

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Ayala

Gottardo

Zuccato

et al. 2020

Sci Rep

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Biochemical determinants of the IGFBP‐3–hyaluronan interaction

et al. 2020

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IGFBP‐3, the most abundant IGFBP and the main carrier of insulin‐like growth factor I (IGF‐I) in the circulation, can bind IGF‐1 with high affinity, which attenuates IGF/IGF‐IR interactions, thereby resulting in antiproliferative effects. The C‐terminal domain of insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) is known to contain an 18‐basic amino acid motif capable of interacting with either humanin (HN) or hyaluronan (HA). We previously showed that the 18‐amino acid IGFBP‐3 peptide is capable of binding either HA or HN with comparable affinities to the full‐length IGFBP‐3 protein and that IGFBP‐3 can compete with the HA receptor, CD44, for binding HA. Blocking the interaction between HA and CD44 reduced viability of A549 human lung cancer cells. In this study, we set out to better characterize IGFBP‐3‐HA interactions. We show that both stereochemistry and amino acid identity are important determinants of the interaction between the IGFBP‐3 peptide and HA and for the peptide's ability to exert its cytotoxic effects. Binding of IGFBP‐3 to either HA or HN was unaffected by glycosylation or reduction of IGFBP‐3, suggesting that the basic 18‐amino acid residue sequence of IGFBP‐3 remains accessible for interaction with either HN or HA upon glycosylation or reduction of the full‐length protein. Removing N‐linked oligosaccharides from CD44 increased its ability to compete with IGFBP‐3 for binding HA, while reduction of CD44 rendered the protein relatively ineffective at blocking IGFBP‐3‐HA interactions. We conclude that both deglycosylation and disulfide bond formation are important for CD44 to compete with IGFBP‐3 for binding HA.

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Interaction of amyloid beta with humanin and acetylcholinesterase is modulated by ATP

et al. 2020

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Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases

Cited by 38 publications

References 100 publications

Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Biochemical determinants of the IGFBP‐3–hyaluronan interaction

Interaction of amyloid beta with humanin and acetylcholinesterase is modulated by ATP

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