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Updated: May 22, 2025

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Intercellular contractile force attenuates chemosensitivity through Notch-MVP-mediated nuclear drug export

Pengyu Du1,2,3,4, Kai Tang1,3, Xi Chen3

  • 1The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China.

Proceedings of the National Academy of Sciences of the United States of America
|May 7, 2025
PubMed

Insights

Tumor cell contractility inversely affects chemotherapy sensitivity. High contractile force reduces drug effectiveness by activating Notch signaling and major vault protein, increasing drug resistance.

Area of Science:

  • Oncology
  • Biophysics
  • Cell Biology

Background:

  • Chemotherapeutic resistance is a major obstacle in cancer treatment, often attributed to biochemical mechanisms.
  • Understanding novel regulatory pathways beyond traditional biochemistry is crucial for improving treatment efficacy.

Purpose of the Study:

  • To investigate the correlation between tumor cell contractility and chemosensitivity.
  • To elucidate the molecular mechanisms linking cellular contractility to drug resistance.
  • To explore the potential of targeting cellular contractility for cancer therapy.

Main Methods:

  • Analysis of clinical biopsies and cancer cell lines.
  • Measurement of actomyosin-mediated contractile force and intercellular force propagation.
  • Investigation of Notch signaling pathway activation and major vault protein expression.
  • In vivo studies using tumor xenografts and assessment of therapeutic interventions.

Main Results:

  • An inverse correlation was found between tumor cell contractility and chemosensitivity.
  • High actomyosin-mediated contractile force attenuates chemotherapy vulnerability via intercellular force propagation.
  • Cell-cell interaction activates Notch signaling, upregulating major vault protein and promoting drug export from nuclei.
  • Inhibition of contractile force, Notch signaling, or major vault protein reversed tumor tolerance to chemotherapy in vivo.
  • Actomyosin-Notch signaling is linked to patient drug resistance and cancer recurrence.

Conclusions:

  • Intercellular force and cellular contractility play a regulatory role in chemotherapy sensitivity.
  • The actomyosin-Notch signaling pathway is a key mediator of chemoresistance.
  • Targeting cellular contractility and associated signaling pathways offers a promising avenue for novel cancer mechanotherapeutics.
Keywords:
cell mechanicschemosensitivitycontractilityintercellular forcemechanotransduction

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