p-21 Activated Kinase as a Molecular Target for Chemoprevention in Diabetes

Kyle Dammann; Vineeta Khare; Clyde Coleman; Henrik Berdel; Christoph Gasche

doi:10.3390/geriatrics3040073

p-21 Activated Kinase as a Molecular Target for Chemoprevention in Diabetes

Geriatrics (Basel). 2018 Oct 19;3(4):73. doi: 10.3390/geriatrics3040073.

Authors

Kyle Dammann¹, Vineeta Khare², Clyde Coleman³, Henrik Berdel⁴, Christoph Gasche⁵

Affiliations

¹ Department of Clinical Medicine, Medical University of the Americas, Devens, MA 01434, USA. dammannkw@gmail.com.
² Department of Internal Medicine III, Medical University of Vienna, Vienna 1090, Austria. vineeta.khare@meduniwien.ac.at.
³ Department of Surgery, University of Kentucky HealthCare, Lexington, KY 40536, USA. ccole2@uky.edu.
⁴ Department of Acute Care and Trauma Surgery, University of Kentucky HealthCare, Lexington, KY 40536, USA. Henrik.Berdel@uky.edu.
⁵ Department of Internal Medicine III, Medical University of Vienna, Vienna 1090, Austria. christoph.gasche@meduniwien.ac.at.

Abstract

Anti-diabetic drugs modulate p-21 activated kinase (PAK) signaling. Introduction: Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease associated with increased cancer risk. PAK signaling is implicated in cellular homeostasis when regulated, and cancer when unrestrained. Recent reports provided a role for PAK signaling in glucose homeostasis, but the role of PAKs in the pathogenesis of T2DM is unknown. Here, we performed a mini-meta-analysis to explore if anti-diabetic drugs modify PAK signaling pathways, and provide insight regarding modulation of these pathways, to potentially reduce diabetes-associated cancer risk. Methods: PAK interacting partners in T2DM were identified using the online STRING database. Correlation studies were performed via systematic literature review to understand the effect of anti-diabetic drugs on PAK signaling. A mini-meta-analysis correlated multiple clinical studies and revealed the overall clinical response rate and percentage of adverse events in piogliazone (n = 53) and metformin (n = 91) treated patients with PAK-associated diseases. Results: A total of 30 PAK interacting partners were identified (10: reduced beta-cell mass; 10: beta-cell dysfunction; 10: obesity-insulin resistance), which were highly associated with Wnt, and G-protein signaling. The anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall, clinical response upon pioglitazone treatment was 53%. Seventy-nine percent of pioglitazone and 75% of metformin treated patients had adverse events. Pioglitazone reduced molecular-PAK biomarkers of proliferation (Ki67 and CyclinD1), and metformin had the opposite effect. Conclusions: PAK signaling in T2DM likely involves Wnt and G-protein signaling, which may be altered by the anti-diabetic drugs metformin and pioglitazone. Apart from the therapeutic limitations of adverse events, pioglitazone may be promising in chemoprevention. However long-term multi-centered studies, which initiate pioglitazone treatment early will be required to fully assess the full potential of these drugs.

Keywords: cancer; chemoprevention; inflammation; metformin; p-21 activated kinase; pioglitazone; type 2 diabetes mellitus.

Publication types

Review