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Reversal of MPPa-PDT Resistance in Osteosarcoma by Targeting ROCK2-Mediated Autophagy

Xuan Yi1,2,3,4, Xueqiang Deng1,5, Jianyong Deng6

  • 1Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, China.

Cell Proliferation
|July 16, 2025
PubMed

Insights

Targeting Rho-associated coiled-coil containing protein kinase 2 (ROCK2) reverses resistance to pyropheophorbide-a methyl ester-Photodynamic therapy (MPPa-PDT) in osteosarcoma. Inhibiting ROCK2 decreases autophagy and restores MPPa-PDT sensitivity, offering new therapeutic strategies for osteosarcoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Osteosarcoma (OS) is a malignant bone tumor with poor prognosis, often developing resistance to treatments like pyropheophorbide-a methyl ester-Photodynamic therapy (MPPa-PDT).
  • Understanding the mechanisms of MPPa-PDT resistance is crucial for improving therapeutic outcomes in osteosarcoma patients.

Purpose of the Study:

  • To investigate the role of Rho-associated coiled-coil containing protein kinase 2 (ROCK2) in MPPa-PDT resistance in osteosarcoma.
  • To elucidate the molecular mechanisms by which ROCK2 influences MPPa-PDT sensitivity, focusing on autophagy and the Hippo signaling pathway.

Main Methods:

  • Assessed ROCK2 expression in osteosarcoma cells post-MPPa-PDT treatment.
  • Investigated the effect of ROCK2 inhibition on osteosarcoma cell sensitivity to MPPa-PDT and cellular autophagy levels.
  • Conducted rescue experiments to confirm ROCK2's role in mediating resistance via autophagy regulation.
  • Analyzed the interaction between ROCK2, SAV1, and MST1 within the Hippo signaling pathway.
  • Correlated ROCK2 expression and Hippo pathway activity with clinical osteosarcoma patient prognosis.

Main Results:

  • ROCK2 expression was upregulated in osteosarcoma cells following MPPa-PDT treatment.
  • Inhibition of ROCK2 sensitized osteosarcoma cells to MPPa-PDT and reduced autophagy.
  • ROCK2 was found to mediate MPPa-PDT resistance by regulating autophagy through the Hippo signaling pathway.
  • ROCK2 competes with MST1 for SAV1 binding, inhibiting Hippo pathway activation and promoting MPPa-PDT resistance.
  • Clinical data confirmed ROCK2 as an independent prognostic factor associated with worse outcomes in osteosarcoma patients.

Conclusions:

  • ROCK2 plays a critical role in mediating MPPa-PDT resistance in osteosarcoma by regulating autophagy via the Hippo signaling pathway.
  • Targeted inhibition of ROCK2, for example, using J059-0149, represents a promising strategy to overcome MPPa-PDT resistance.
  • This study provides novel therapeutic targets and insights for enhancing the clinical efficacy of MPPa-PDT in osteosarcoma treatment.
Keywords:
MPPa‐PDTROCK2autophagyhippo pathwayosteosarcoma

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