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Updated: Oct 6, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

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Osteosarcoma cell proliferation suppression via SHP-2-mediated inactivation of the JAK/STAT3 pathway by

Dongrong Zhu1, Chen Chen1, Xiaoqin Liu1

  • 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.

Journal of Advanced Research
|January 13, 2022
PubMed
Abstract

Insights

Tubocapsenolide A (TA) demonstrates significant anti-tumor effects against osteosarcoma by directly activating SHP-2 phosphatase. This activation inhibits the JAK/STAT3 pathway, offering a potential new therapeutic strategy for osteosarcoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tubocapsenolide A (TA), a withanolide-type steroid, exhibits potent anti-proliferative activity.
  • The specific effects of TA on the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway and its therapeutic potential in osteosarcoma remain uninvestigated.

Purpose of the Study:

  • To investigate the anti-osteosarcoma effects of Tubocapsenolide A (TA).
  • To elucidate the molecular mechanisms underlying TA's action, focusing on the JAK/STAT3 pathway and its interaction with SHP-2.

Main Methods:

  • In vitro assays (colony formation, EDU staining, cell cycle/apoptosis) were used to assess TA's biological functions in U2OS cells.
  • Enzyme activity assays, DARTS, CETSA, and BLI were employed to detect TA's interaction with SHP-2.
  • In vivo anti-tumor efficacy was evaluated in a xenograft tumor model, with protein expression analyzed via Western blotting.

Main Results:

  • TA demonstrated significant anti-osteosarcoma activity both in vitro and in vivo, mediated by the JAK/STAT3 signaling pathway.
  • TA directly interacted with and activated the phosphatase activity of SHP-2.
  • Inhibition of SHP-2 or the JAK/STAT3 pathway reversed TA's anti-proliferative effects and restored TA-induced cell death.

Conclusions:

  • TA activates SHP-2 phosphatase activity, leading to JAK/STAT3 pathway inhibition and contributing to its anti-tumor efficacy in osteosarcoma.
  • These findings position TA as a promising novel therapeutic agent for osteosarcoma treatment.
Keywords:
JAK/STAT3OsteosarcomaSHP-2Tubocapsenolide A

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