Related Experiment Video

Updated: Sep 14, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

18.1K

Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in

Ruimei Ren1, Shan Zhang2, Zhan Peng1

  • 1Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Cell Death & Disease
|July 20, 2025
PubMed

Insights

Tumor extracellular matrix (ECM) stiffness, not previously recognized, drives sorafenib resistance in hepatocellular carcinoma (HCC). Reducing ECM stiffness enhances sorafenib efficacy by targeting the ITGB1-PI3K/AKT-G6PD pathway.

Area of Science:

  • Oncology
  • Biochemistry
  • Biophysics

Background:

  • Sorafenib is a key drug for advanced hepatocellular carcinoma (HCC), but resistance limits its effectiveness.
  • Understanding resistance mechanisms is vital for improving antiangiogenic therapy outcomes.
  • Extracellular matrix (ECM) stiffness is a potential, unexplored factor in HCC chemoresistance.

Purpose of the Study:

  • To investigate the role of ECM stiffness in sorafenib resistance in HCC.
  • To identify the molecular pathways linking ECM stiffness to sorafenib resistance.
  • To explore ECM stiffness modulation as a therapeutic strategy for overcoming sorafenib resistance.

Main Methods:

  • Atomic force microscopy to measure ECM stiffness in HCC patient tumor samples.
  • Orthotopic xenograft models in mice to assess the impact of ECM stiffness reduction on sorafenib efficacy.
  • In vitro and in vivo experiments to elucidate the molecular mechanisms involving ECM stiffness, G6PD, and the ITGB1-PI3K/AKT pathway.
  • Clinical tissue microarray analysis to correlate molecular markers with sorafenib resistance.

Main Results:

  • Higher ECM stiffness was observed in sorafenib-resistant HCC patients compared to responders.
  • Inhibiting lysyl oxidase (LOX) to reduce ECM stiffness significantly enhanced sorafenib efficacy in a mouse model.
  • ECM stiffness upregulates glucose-6-phosphate dehydrogenase (G6PD) expression via the ITGB1-PI3K/AKT pathway, mediating sorafenib resistance.
  • Expression of collagen I, α-SMA, ITGB1, p-AKT, and G6PD correlated with sorafenib resistance in HCC patients.

Conclusions:

  • Tumor ECM stiffness is a significant factor contributing to sorafenib resistance in HCC.
  • Targeting ECM stiffness, potentially by inhibiting LOX, can re-sensitize HCC to sorafenib.
  • The ITGB1-PI3K/AKT-G6PD signaling axis represents a promising therapeutic target for overcoming sorafenib resistance in HCC.

More Related Videos

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

13.3K
Live-Cell Förster Resonance Energy Transfer Imaging of Metabolically Regulated Akt Activation Dynamics in HepG2 Cells08:03

Live-Cell Förster Resonance Energy Transfer Imaging of Metabolically Regulated Akt Activation Dynamics in HepG2 Cells

Published on: May 23, 2025

270

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
9.3K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.5K
Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
13.9K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.7K