Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy

Abstract

Cell behaviors, including proliferation, differentiation and apoptosis, are intricately controlled during organ development and tissue regeneration. In the past 9 years, the Hippo signaling pathway has been delineated to play critical roles in organ size control, tissue regeneration and tumorigenesis through regulating cell behaviors. In mammals, the core modules of the Hippo signaling pathway include the MST1/2-LATS1/2 kinase cascade and the transcriptional co-activators YAP/TAZ. The activity of YAP/TAZ is suppressed by cytoplasmic retention due to phosphorylation in the canonical MST1/2-LATS1/2 kinase cascade-dependent manner or the non-canonical MST1/2- and/or LATS1/2-independent manner. Hippo signaling pathway, which can be activated or inactivated by cell polarity, contact inhibition, mechanical stretch and extracellular factors, has been demonstrated to be involved in development and tumorigenesis of liver and pancreas. In addition, we have summarized several small molecules currently available that can target Hippo-YAP pathway for potential treatment of hepatic and pancreatic cancers, providing clues for other YAP initiated cancers therapy as well.

Modular and Adaptable Tumor Niche Prepared from Visible Light Initiated Thiol-Norbornene Photopolymerization

“…7B) were evaluated because of their roles in tumor/organ size control, as well as in maintaining stemness in cancer stem cells (CSC). 25, 29-32 Moreover, the expression of matrix metalloproteinase 14 (MMP14, Fig. 7C) was examined because of its importance in matrix cleavage during the growth of tumor spheres.…”

Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway

“…Our first strategy to obtain dipyrrin 1 (Scheme 1) was inspired by the total synthesis of hematoporphyrin published by Martine tal. [16] Thec ondensation of the two pyrrolo units (2 [17] and 3 [18] )u sing HBr in acetic acid gave dipyrrin 4 in high yield (89 %), but reduction of the acetylg roup in the presence of NaBH 4 [15] alone or with CeCl 3 , [19] yieldedd ipyrromethane 5' instead of the expected alcohol (5).…”

“…YAPa nd TAZ, the downstream effectors of the Hippo pathway, interactw ith TEAD to regulate stem cell proliferation,t issue growth, and organ size. [1] Oncogenic YAP/TAZ are overexpressed in many cancers, [2][3][4][5] causing overgrowth phenotypes and metastasis. Liu-Chittenden and colleagues [6] were the first to demonstrate the feasibility of disrupting the YAP/TEAD complex as ap ertinent therapeutic strategy in cancert herapy and identified three members of the porphyrin family-verteporfin (VP), protoporphyrin IX (PPIX), and hematoporphyrin (HP)-as inhibitors of YAP/TEAD-dependent transcription.V Pw as found to be the most effective compound to inhibit the complex between YAPa nd TEAD2 andw as used for in vivo validation.…”

Designing Visible Light‐Cured Thiol‐Acrylate Hydrogels for Studying the HIPPO Pathway Activation in Hepatocellular Carcinoma Cells

“…The HIPPO pathway is a key signaling cascade that controls organ size, cell proliferation and differentiation . It was reported that YAP, the HIPPO pathway effector, localizes in the cytoplasm when cells are cultured on top of softer environmental matrices; whereas when cells are seeded on stiffer surfaces, YAP translocalizes into the nucleus .…”

“…Although still significantly lower than the 2D counterparts, the presence of integrin‐binging motif RGDS in 3D hydrogels enhanced the CTGF mRNA level in both softer (0.1% NVP, 1 × 10 −3 m RGD) and stiffer (0.2% NVP, 1 × 10 −3 m RGD) cell‐laden hydrogels, suggesting a role of cell‐matrix interaction in regulating YAP activation. The HIPPO pathway controls organ size and cell proliferation . Activated HIPPO pathway phosphorylates YAP, causing its cytoplasmic retention and degradation.…”