RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues.

Abstract

Aberrant activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR and Ras/mitogen-activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain-containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild-type mice by hydrodynamic tail vein injection combined with sleeping beauty-mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce HCCs in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of fatty acid synthase and stearoyl-CoA desaturase-1 (SCD1). Galectin-1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co-inhibitory treatment with PIK3CA inhibitors and the galectin-1 inhibitor OTX008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues.

• Authors: Alexander Scheiter, Katja Evert, Lucas Reibenspies, Antonio Cigliano, Katharina Annweiler, Karolina Müller, Laura-Maria-Giovanna Pöhmerer, Hongwei Xu, Guofei Cui, Timo Itzel, Silvia Materna-Reichelt, Andrea Coluccio, Kamran Honarnejad, Andreas Teufel, Christoph Brochhausen, Frank Dombrowski, Xin Chen, Matthias Evert, Diego F Calvisi, Kirsten Utpatel
• Journal: Molecular oncology (Mol Oncol) Vol. 16 Issue 5 Pg. 1091-1118 (03 2022) ISSN: 1878-0261 [Electronic] United States
• PMID: 34748271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• Galectin 1
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Pik3ca protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Carcinogenesis
• Carcinoma, Hepatocellular (genetics, pathology)
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Galectin 1 (genetics)
• Humans
• Liver Neoplasms (genetics, pathology)
• Mice
• Mutation
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Up-Regulation