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

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Department of Clinical Medicine, Medical University of the Americas, Devens, MA 01434, USA
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Department of Internal Medicine III, Medical University of Vienna, Vienna 1090, Austria
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Department of Surgery, University of Kentucky HealthCare, Lexington, KY 40536, USA
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Department of Acute Care and Trauma Surgery, University of Kentucky HealthCare, Lexington, KY 40536, USA
*
Author to whom correspondence should be addressed.
Running Title: PAK1 in chemoprevention and diabetes.
Geriatrics 2018, 3(4), 73; https://doi.org/10.3390/geriatrics3040073
Received: 18 September 2018 / Revised: 12 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
Hypothesis: 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. View Full-Text
Keywords: p-21 activated kinase; pioglitazone; metformin; type 2 diabetes mellitus; cancer; chemoprevention; inflammation p-21 activated kinase; pioglitazone; metformin; type 2 diabetes mellitus; cancer; chemoprevention; inflammation
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Dammann, K.; Khare, V.; Coleman, C.; Berdel, H.; Gasche, C. p-21 Activated Kinase as a Molecular Target for Chemoprevention in Diabetes. Geriatrics 2018, 3, 73.

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