Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Abstract

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

Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer

“…We grouped results from knnDREMI into three gene modules corresponding to low (module 1), medium (module 2), and high PLCG2 expression (module 3) (Figure S3E; Table S12). Candidate genes in module 3 included FGFR1 (implicated in SCLC through frequent amplifications [Elakad et al, 2020]), and MTRNR2L8 and MTRNR2L12 (humanin family genes shown to inhibit apoptosis [Morris et al, 2020], to be neuroprotective in Alzheimer disease [Kusakari et al, 2018], and to promote tumor progression in triple-negative breast cancer (TNBC) [Moreno Ayala et al, 2020]). Among the top 5% of pathways most correlated to module 3 were those related to stemness (including OCT4 and SOX2 targets), metastatic gene signatures, and prometastatic signaling pathways (including Wnt and BMP signaling) (Dongre and Weinberg, 2019) (Figures S3E and S3F; Table S13).…”

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets

“…It was defined that HN was upregulated in TNBC (triple-negative breast cancer) model biopsies. Application of HN in a TNBC mice model leads to a reduction in the tumour apoptotic rate, stimulates tumour progression, growth and lung metastases development, thus abating chemotherapy effects [90]. Thereby, HN may have tumour-stimulation activity and a tumour HN-blocking strategy could be considered as a possible target to increase the efficacy of chemotherapy in breast cancer treatment.…”

Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration

“…Neuronal cells Mice HNG Removal of abnormal proteins via chaperone-mediated autophagy [ 91 ] Cardiovascular disease Platelets Mice HNG Attenuated cremaster arterial thrombus formation [ 96 ] Aging C. elegans Worm HN Increased lifespan [ 97 ] Cancer Blood plasma, testes Mice HNG Cytoprotection of germ cells and leukocytes and non-cancerous cells in tumor-bearing mice. [ 98 ] Neuroblastoma or medulloblastoma Growth plate tissues/metatarsal bones/tumor xenografts Human, Mice HNG Prevention of bone growth impairment and chondrocyte apoptosis [ 99 ] Cancer Breast cancer cells Human, Mice HN Pro-tumoral effects [ 100 ] Cancer and fertility Blood, liver, spleen, testes Mice HNG Amelioration of chemotherapy-induced germ cell apoptosis; WBC and granulocyte loss. [ 101 ] Neurodegenerative diseases.…”