Preprint Review Version 1 This version is not peer-reviewed

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

Version 1 : Received: 18 September 2018 / Approved: 19 September 2018 / Online: 19 September 2018 (00:50:05 CEST)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Geriatrics 2018, 3, 73
DOI: 10.3390/geriatrics3040073

Abstract

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 online STRING database. Correlation studies were performed via systematic literature review to understand the effect of anti-diabetic drugs on PAK signaling. 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. Anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall clinical response upon pioglitazone treatment was 53%. 79% 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 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.

Subject Areas

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

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