Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM.

ATX-101, a peptide targeting PCNA, has antitumor efficacy alone or in combination with radiotherapy in murine models of human glioblastoma / Gravina, G. L.; Colapietro, A.; Mancini, A.; Rossetti, A.; Martellucci, S.; Ventura, L.; Di Franco, M.; Marampon, F.; Mattei, V.; Biordi, L. A.; Otterlei, M.; Festuccia, C.. - In: CANCERS. - ISSN 2072-6694. - 14:2(2022). [10.3390/cancers14020289]

ATX-101, a peptide targeting PCNA, has antitumor efficacy alone or in combination with radiotherapy in murine models of human glioblastoma

Gravina G. L.
Primo
;
Martellucci S.;Marampon F.;
2022

Abstract

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM.
APIM-peptide; DNA damage signaling; GBM
01 Pubblicazione su rivista::01a Articolo in rivista
ATX-101, a peptide targeting PCNA, has antitumor efficacy alone or in combination with radiotherapy in murine models of human glioblastoma / Gravina, G. L.; Colapietro, A.; Mancini, A.; Rossetti, A.; Martellucci, S.; Ventura, L.; Di Franco, M.; Marampon, F.; Mattei, V.; Biordi, L. A.; Otterlei, M.; Festuccia, C.. - In: CANCERS. - ISSN 2072-6694. - 14:2(2022). [10.3390/cancers14020289]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1610420
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