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

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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.

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Acknowledgements

We are grateful to Prof. K. Pantopoulos (McGill University, Montreal, Quebec, Canada) for offering tTA-HepG2 cells. A.K. is supported by a fellowship from States Scholarship Foundation (ΙΚΥ). This work was partially supported by the “ARISTEIA ΙΙ” Action of the “OPERATIONAL PROGRAM EDUCATION AND LIFELONG LEARNING” (HYPOXYTARGET 3129 to G.S.) co-funded by the European Social Fund (ESF) and National Resources and by a Research Grant in Biomedical Sciences funded by Fondation Santé (5360 to I.M.).

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  1. Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece

    Angeliki Karagiota, Maria Kourti, George Simos & Ilias Mylonis

  2. Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Canada

    George Simos

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IM and GS conceived the study and carried out its design. AK and MK performed the experiments. AK, GS and IM analyzed data and wrote the paper. All authors read and approved the final manuscript.

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Karagiota, A., Kourti, M., Simos, G. et al. HIF-1α-derived cell-penetrating peptides inhibit ERK-dependent activation of HIF-1 and trigger apoptosis of cancer cells under hypoxia. Cell. Mol. Life Sci. 76, 809–825 (2019). https://doi.org/10.1007/s00018-018-2985-7

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