2. Academic Validation
  3. Reversal of MPPa-PDT Resistance in Osteosarcoma by Targeting ROCK2-Mediated Autophagy

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

  • Cell Prolif. 2025 Jul 16:e70097. doi: 10.1111/cpr.70097.
Xuan Yi 1 2 3 4,  Xueqiang Deng 1 5,  Jianyong Deng 6,  Chen Li 1 2 3 4,  Hong Peng 7 8,  Yunyan Du 9,  Qing Li 10,  Xiaohua Yan 11,  Xin Hu 12,  Yan Zheng 13,  Shenliang Chen 1 2 3 4,  Ting Xiong 1 2 3 4,  Debin Xu 14,  Leifeng Chen 15 16,  Liang Hao 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 2 Institute of Orthopedics of Jiangxi Province, Nanchang, China.
  • 3 Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Nanchang, China.
  • 4 Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, China.
  • 5 Department of Rehabilitation, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 6 Department of Vascular & Interventional & Lymphatic Surgery, The First Hospital of Nanchang, Nanchang, China.
  • 7 Department of Anorectal Surgery, Changcheng Hospital Affiliated to Nanchang University, Nanchang, China.
  • 8 Department of Anorectal Surgery, No 908th Hospital of Chinese, Nanchang, China.
  • 9 Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China.
  • 10 Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 11 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 12 Department of Orthopedics, Pingxiang People's Hospital, PingXiang, China.
  • 13 Department of Medical Genetics, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 14 Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 15 Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 16 Medical Center for Cardiovascular Diseases, Neurological Diseases and Tumors of Jiangxi Province, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
PMID: 40670295 DOI: 10.1111/cpr.70097
Abstract

Osteosarcoma (OS) is a primary bone tumour that occurs mostly in adolescents and is associated with a high degree of malignancy, early metastasis, and poor prognosis. Pyropheophorbide-a methyl ester-Photodynamic therapy (MPPa-PDT) is a new approach for the clinical treatment of osteosarcoma that develops after surgery and radiotherapy; however, the presence of MPPa-PDT resistance in osteosarcoma greatly limits its efficacy. In this study, we found that Rho-associated coiled-coil containing protein kinase 2 (ROCK2) expression increased in osteosarcoma cells after MPPa-PDT treatment. ROCK2 inhibition results in osteosarcoma sensitivity to MPPa-PDT and is accompanied by a decrease in cellular Autophagy levels. Rescue experiments further showed that ROCK2 mediates MPPa-PDT resistance in osteosarcoma by regulating Autophagy. Mechanistic studies have shown that ROCK2 mediates Autophagy in osteosarcoma cells by regulating the Hippo signalling pathway. ROCK2 overexpression resulted in increased levels of the ROCK2-Salvador homology 1 (SAV1) complex and decreased levels of the mammalian STE20-like protein kinase 1 (MST1)-SAV1 complex, thereby inhibiting activation of the Hippo pathway, which in turn led to osteosarcoma MPPa-PDT resistance by regulating cellular Autophagy. ROCK2 competes with MST1 for binding to the aa 28-198 region of SAV1. We also confirmed from a clinical perspective that ROCK2 is an independent prognostic factor in patients with osteosarcoma, is associated with worse patient prognosis, and correlates with the Hippo pathway. Targeted inhibition of ROCK2 by screening for J059-0149 increases the sensitivity of osteosarcoma to MPPa-PDT. In conclusion, our study establishes a novel mechanism to reverse MPPa-PDT resistance in osteosarcoma by targeting ROCK2-mediated Autophagy, providing new targets and research ideas for the clinical treatment of osteosarcoma MPPa-PDT resistance.

Keywords

MPPa‐PDT; ROCK2; autophagy; hippo pathway; osteosarcoma.

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