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Protein kinase D: Integrating cancer and metabolic disorders

A Shemy1, B Sanchez2, H Mizuno3

  • 1KU Leuven, Department of Chemistry, Laboratory for Biomolecular Modelling and Design, Celestijnenlaan 200G, box 2403, B-3001, Leuven, Belgium.

Molecular Aspects of Medicine
|January 26, 2026
PubMed

Insights

Protein Kinase D (PKD) isoforms link obesity and type II diabetes mellitus to cancer. This review details how PKD1, PKD2, and PKD3 impact metabolic disorders and tumor growth, suggesting targeted therapies for related cancers.

Area of Science:

  • Molecular Biology
  • Oncology
  • Metabolic Disorders

Background:

  • Obesity and type II diabetes mellitus (T2DM) are strongly associated with increased cancer risk.
  • Protein Kinase D (PKD) isoforms (PKD1, PKD2, PKD3) are key signaling molecules in metabolic and oncogenic pathways.
  • Understanding the specific roles of each PKD isoform is crucial for deciphering their involvement in disease.

Purpose of the Study:

  • To review the isoform-specific functions of Protein Kinase D (PKD) in the pathophysiology of metabolic disorders and cancer.
  • To explore how metabolic dysregulation, driven by obesity and T2DM, influences PKD signaling in cancer.
  • To identify potential therapeutic strategies targeting PKD isoforms in cancer patients with metabolic comorbidities.

Main Methods:

  • Literature review synthesizing current research on PKD isoforms, metabolic disorders, and cancer.
  • Analysis of studies detailing the molecular mechanisms of PKD1, PKD2, and PKD3 in cellular and tissue contexts.
  • Examination of how obesity- and diabetes-related factors modulate PKD signaling pathways.

Main Results:

  • PKD1 has a dual role in cancer, acting as a tumor suppressor in some contexts and pro-tumorigenic in others, while influencing insulin secretion, lipogenesis, and thermogenesis.
  • PKD2 promotes tumor progression via hypoxia signaling, matrix remodeling, and immune evasion by regulating HIF-1α, Snail, β-catenin, and PD-L1.
  • PKD3 enhances cancer cell proliferation and metabolic reprogramming, particularly glycolysis, and modulates hepatic insulin/glucagon signaling.

Conclusions:

  • Metabolic factors associated with obesity and T2DM amplify PKD signaling, reinforcing the link between metabolic health and cancer.
  • PKD isoforms, especially PKD2 and PKD3, represent promising therapeutic targets for cancers influenced by metabolic dysfunction.
  • Future strategies may involve isoform-specific PKD inhibitors to selectively target tumor invasion, immune evasion, and metabolic reprogramming.
Keywords:
CancerDiabetesMetabolic disordersMetastasisObesityProtein kinase D

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