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Cell Mol Life Sci. 2019 Feb;76(4):809-825. doi: 10.1007/s00018-018-2985-7. Epub 2018 Dec 10.

HIF-1α-derived cell-penetrating peptides inhibit ERK-dependent activation of HIF-1 and trigger apoptosis of cancer cells under hypoxia.

Author information

1
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece.
2
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece. simos@med.uth.gr.
3
Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Canada. simos@med.uth.gr.
4
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece. mylonis@med.uth.gr.

Abstract

Hypoxia is frequently encountered in the microenvironment of solid tumors. Hypoxia-inducible factors (HIFs), the main effectors of cell response to hypoxia, promote cancer cell survival and progression. HIF-1α, the oxygen-regulated subunit of HIF-1, is often correlated with oncogenesis and represents an attractive therapeutic target. We have previously reported that activation HIF-1α by ERK involves modification of two serine residues and masking of a nuclear export signal (NES), all inside a 43-amino acid domain termed ERK Targeted Domain (ETD). Overexpression of ETD variants including wild-type, phospho-mimetic (SE) or NES-less (IA) mutant forms caused HIF-1 inactivation in two hepatocarcinoma cell lines, while a phospho-deficient (SA) form was ineffective and acted as a sequence-specific negative control. To deliver these ETD forms directly into cancer cells, they were fused to the HIV TAT-sequence and produced as cell-permeable peptides. When the TAT-ETD peptides were added to the culture medium of Huh7 cells, they entered the cells and, with the exception of ETD-SA, accumulated inside the nucleus, caused mislocalization of endogenous HIF-1α to the cytoplasm, significant reduction of HIF-1 activity and inhibition of expression of specific HIF-1, but not HIF-2, gene targets under hypoxia. More importantly, transduced nuclear TAT-ETD peptides restricted migration, impaired colony formation and triggered apoptotic cell death of cancer cells grown under hypoxia, while they produced no effects in normoxic cells. These data demonstrate the importance of ERK-mediated activation of HIF-1 for low oxygen adaptation and the applicability of ETD peptide derivatives as sequence-specific HIF-1 and cancer cell growth inhibitors under hypoxia.

KEYWORDS:

Cancer; Cell-penetrating peptides; ERK1/2; HIF-1; Hypoxia

PMID:
30535970
DOI:
10.1007/s00018-018-2985-7
[Indexed for MEDLINE]

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