Video Experimental Relacionado

Updated: Sep 10, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

El oncometabolito 5-IP inhibe la inositol 5-fosfatasa para permitir la endocitosis de la E-caderina

Hongyun Zhang¹, Bobo Zhang¹, Yuebo Zhao¹

¹School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Nature chemical biology

|August 26, 2025

Resumen

Un metabolito llamado 5-difosfoinositol pentakisfosfato (5-IP7) impulsa la pérdida de E-cadherina en el cáncer colorrectal promoviendo la endocitosis. Dirigirse a IP6K2, que produce 5-IP7, puede proteger la barrera intestinal contra la inflamación y el cáncer.

Área de la Ciencia:

Biología celular
Biología del cáncer
Metabolomía

Sus antecedentes:

La regulación a la baja de la E-cadherina es una característica de la transición epitelial-mesenquimal, típicamente vinculada a la represión transcripcional.
El cáncer colorrectal asociado a la inflamación (CRC) presenta mecanismos únicos para la pérdida de E-cadherina.
La integridad de la unión de adherentes (AJ) es crucial para la función de la barrera epitelial.

Objetivo del estudio:

Investigar una vía impulsada por los metabolitos para la regulación a la baja de la E-cadherina en el cáncer colorrectal asociado a la inflamación.
Aclarar el papel de la IP6 quinasa-2 (IP6K2) y su producto pentakisfosfato de 5-difosfoinositol (5-IP7) en la endocitosis de la E-cadherina.
Explorar el potencial terapéutico de dirigirse a IP6K2 en el CCR y la colitis.

Principales métodos:

Se utilizó un modelo de dextrano sulfato de sodio (DSS) para inducir la inflamación y la colitis/CRC en ratones.
Investigó la activación de IP6K2 a través de un eje de fosforilación ROS-Src.
Se examinó el efecto del 5-IP7 sobre las inositol 5-fosfatasas (por ejemplo, OCRL) y los niveles de PI (4,5) P2.
Se evaluó el impacto de la deleción de IP6K2 y la inhibición farmacológica en la integridad de la AJ y la progresión de la enfermedad.

Principales resultados:

IP6K2, regulado al alza en pacientes con CCR, genera 5-IP7, promoviendo la endocitosis de la E-cadherina y la activación de la β-catenina a través de la señalización ROS-Src.
5-IP7 inhibe la OCRL, lo que lleva a la acumulación de PI (4, 5) P2 y al reclutamiento de adaptadores endocíticos.
El agotamiento de 5-IP7 o un mutante no vinculante de OCRL confirió resistencia a la interrupción de la AJ inducida por DSS.
La deleción intestinal de IP6K2 atenuó la colitis inducida por DSS/CRC; un inhibidor de IP6K2 protegido en ratones de tipo salvaje.

Conclusiones:

5-IP7 actúa como un oncometabolito, aliviando un punto de control endocítrico para impulsar el desmontaje de AJ y promover la CRC.
Dirigirse a IP6K2 ofrece una estrategia potencial para reforzar la barrera epitelial intestinal contra la inflamación y el cáncer.
Este estudio revela un nuevo mecanismo impulsado por los metabolitos para la pérdida de E-cadherina en el cáncer colorrectal.

Más Videos Relacionados

Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry

Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry

Published on: July 26, 2019

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

Videos de Conceptos Relacionados

Inhibition of Cdk Activity

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

Eukaryotic Transcription Inhibitors

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...

Phosphoinositides and PIPs

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...

Anaphase Promoting Complex

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...

Cancer Cell Migration through Invadopodia

Cancer Cell Migration through Invadopodia

Invadosome is a broad category of cell surface structures with proteolytic activity that degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However,...

IP3/DAG Signaling Pathway

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...