A small molecule targeting the interaction between human papillomavirus E7 oncoprotein and cellular phosphatase PTPN14 exerts antitumoral activity in cervical cancer cells.

Abstract

Human papillomavirus (HPV)-induced cancers still represent a major health issue for worldwide population and lack specific therapeutic regimens. Despite substantial advancements in anti-HPV vaccination, the incidence of HPV-related cancers remains high, thus there is an urgent need for specific anti-HPV drugs. The HPV E7 oncoprotein is a major driver of carcinogenesis that acts by inducing the degradation of several host factors. A target is represented by the cellular phosphatase PTPN14 and its E7-mediated degradation was shown to be crucial in HPV oncogenesis. Here, by exploiting the crystal structure of E7 bound to PTPN14, we performed an in silico screening of small-molecule compounds targeting the C-terminal CR3 domain of E7 involved in the interaction with PTPN14. We discovered a compound able to inhibit the E7/PTPN14 interaction in vitro and to rescue PTPN14 levels in cells, leading to a reduction in viability, proliferation, migration, and cancer-stem cell potential of HPV-positive cervical cancer cells. Mechanistically, as a consequence of PTPN14 rescue, treatment of cancer cells with this compound altered the Yes-associated protein (YAP) nuclear-cytoplasmic shuttling and downstream signaling. Notably, this compound was active against cervical cancer cells transformed by different high-risk (HR)-HPV genotypes indicating a potential broad-spectrum activity. Overall, our study reports the first-in-class inhibitor of E7/PTPN14 interaction and provides the proof-of-principle that pharmacological inhibition of this interaction by small-molecule compounds could be a feasible therapeutic strategy for the development of novel antitumoral drugs specific for HPV-associated cancers.

• Authors: Chiara Bertagnin, Lorenzo Messa, Matteo Pavan, Marta Celegato, Mattia Sturlese, Beatrice Mercorelli, Stefano Moro, Arianna Loregian
• Journal: Cancer letters (Cancer Lett) Vol. 571 Pg. 216331 (09 01 2023) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 37532093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Papillomavirus E7 Proteins
• Oncogene Proteins, Viral
• PTPN14 protein, human
• Protein Tyrosine Phosphatases, Non-Receptor

Topics

• Female
• Humans
• Uterine Cervical Neoplasms (drug therapy, genetics, metabolism)
• Human Papillomavirus Viruses
• Papillomavirus E7 Proteins (metabolism)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Papillomavirus Infections (drug therapy)
• Oncogene Proteins, Viral (metabolism)
• Protein Tyrosine Phosphatases, Non-Receptor