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Updated: Jun 28, 2025

Real-Time Quantitative Measurement of Tumor Cell Migration and Invasion Following Synthetic mRNA Transfection
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Real-Time Quantitative Measurement of Tumor Cell Migration and Invasion Following Synthetic mRNA Transfection

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CK2α-mediated phosphorylation of GRP94 facilitates the metastatic cascade in triple-negative breast cancer

Hye-Youn Kim1, Young-Mi Kim1, Suntaek Hong2

  • 1Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, 21999, Republic of Korea.

Cell Death Discovery
|April 22, 2024
PubMed

Insights

Glucose-regulated protein 94 (GRP94) drives triple-negative breast cancer (TNBC) metastasis. Inhibiting its phosphorylation by CK2α with benzamidine may offer a new therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Distant metastasis significantly contributes to the high mortality rate in triple-negative breast cancer (TNBC).
  • The precise role and mechanisms of glucose-regulated protein 94 (GRP94) in cancer metastasis are not fully understood.
  • Increased GRP94 expression is observed in TNBC and correlates with metastatic progression and poor patient prognosis.

Purpose of the Study:

  • To elucidate the biological functions and molecular mechanisms of GRP94 in triple-negative breast cancer (TNBC) metastasis.
  • To investigate the therapeutic potential of targeting GRP94 in TNBC.

Main Methods:

  • Assessed GRP94 expression in TNBC tissues and correlated it with patient prognosis.
  • Utilized GRP94 depletion and overexpression in cell lines to evaluate its functional role in tumorigenesis and metastasis.
  • Investigated the molecular mechanism involving casein kinase 2 alpha (CK2α) phosphorylation of GRP94, its stability, LRP6 interaction, and Wnt signaling activation.
  • Tested the efficacy of benzamidine, a CK2α inhibitor, in preclinical models.

Main Results:

  • GRP94 expression was elevated in TNBC and linked to metastasis and poor prognosis.
  • GRP94 depletion reduced TNBC tumorigenesis and lung metastasis, while its overexpression enhanced invasiveness and metastasis in other breast cancer cells.
  • CK2α phosphorylates GRP94 at serine 306, increasing its stability and LRP6 interaction, thereby activating Wnt signaling.
  • Benzamidine treatment suppressed GRP94 phosphorylation, LRP6 stabilization, and TNBC metastasis.

Conclusions:

  • CK2α-mediated GRP94 phosphorylation is critical for TNBC metastasis via Wnt signaling activation.
  • GRP94 represents a promising therapeutic target for inhibiting TNBC metastasis.

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