Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity.

Abstract

Tumor suppressor genes are frequently silenced in cancer cells by enzymes catalyzing epigenetic histone modifications. The peptidylarginine deiminase family member PAD4 (also called PADI4) is markedly overexpressed in a majority of human cancers, suggesting that PAD4 is a putative target for cancer treatment. Here, we have generated novel PAD inhibitors with low micromolar IC(50) in PAD activity and cancer cell growth inhibition. The lead compound YW3-56 alters the expression of genes controlling the cell cycle and cell death, including SESN2 that encodes an upstream inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Guided by the gene expression profile analyses with YW3-56, we found that PAD4 functions as a corepressor of p53 to regulate SESN2 expression by histone citrullination in cancer cells. Consistent with the mTORC1 inhibition by SESN2, the phosphorylation of its substrates including p70S6 kinase (p70S6K) and 4E-BP1 was decreased. Furthermore, macroautophagy is perturbed after YW3-56 treatment in cancer cells. In a mouse xenograft model, YW3-56 demonstrates cancer growth inhibition activity with little if any detectable adverse effect to vital organs, whereas a combination of PAD4 and histone deacetylase inhibitors further decreases tumor growth. Taken together, our work found that PAD4 regulates the mTORC1 signaling pathway and that PAD inhibitors are potential anticancer reagents that activate tumor suppressor gene expression alone or in combination with histone deacetylase inhibitors.

• Authors: Yuji Wang, Pingxin Li, Shu Wang, Jing Hu, Xiangyun Amy Chen, Jianhui Wu, Megan Fisher, Kira Oshaben, Na Zhao, Ying Gu, Dong Wang, Gong Chen, Yanming Wang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 31 Pg. 25941-53 (Jul 27 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22605338 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Multiprotein Complexes
• Nuclear Proteins
• Proteins
• SESN2 protein, human
• TP53 protein, human
• Tumor Suppressor Protein p53
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Hydrolases
• PADI4 protein, human
• Protein-Arginine Deiminase Type 4
• Protein-Arginine Deiminases
• peptidylarginine deiminase 4, mouse

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology, therapeutic use)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydrolases (antagonists & inhibitors, metabolism)
• Inhibitory Concentration 50
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Multiprotein Complexes
• Nuclear Proteins (genetics, metabolism)
• Protein-Arginine Deiminase Type 4
• Protein-Arginine Deiminases
• Proteins (metabolism)
• Sarcoma (drug therapy, pathology)
• Signal Transduction
• TOR Serine-Threonine Kinases
• Transcriptional Activation (drug effects)
• Tumor Burden (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays