p-21 activated kinase 1 promotes intestinal tumor initiation

MUA Research Day Kyle DammannOctober 3, 2015

Introduction

• p-21 Activated kinase 1 (PAK1)– Serine/threonine kinase effector of RAC1/CDC42• Facilitates β-catenin signaling

– Overexpressed in gastrointestinal cancer– Molecular target of anti-inflammatory drug 5-ASA

Khare et al. Biochem pharmacol. 2013

PAK1– Serine/threonine kinase effector of RAC1/CDC42

Dammann et al. Gut. 2014

Dammann et al. Gut. 2014

PAK1

– Facilitates Wnt/β-catenin signalling

What is the role of PAK1 in intestinal inflammation?

Khare, Dammann et al. IBD. 2015

Proliferation Apoptosis

• PAK1 is a target of anti-inflammatory drug 5-ASA– 5-ASA reduced tumorigenesis, PAK1 overexpression, and β-

catenin signaling in polyps in APCmin mice (Khare et al. Biochem pharmacol. 2013)

• Does 5-ASA’s effect on tumorigenesis and Wnt signalling require PAK1 inhibition?– PAK1 deletion in 2 models of CRC

• APCmin and APCmin/ PAK1-/- mice• AOM/DSS model in WT and PAK1-/- mice

– 1 I.P. injection of 10 mg/kg AOM and 4 cycles of 1.7% DSS– ± 500mg/kg 5-ASA chow

What is the role of PAK1 in CRC?

PAK1 deletion in APCmin mice

(n=10) (n=18)

PAK1 deletion in APCmin mice

Dammann et al. Cancer Prev Res. 2015.

PAK1 deletion in APCmin mice

Dammann et al. Cancer Prev Res. 2015.

PAK1 deletion in AOM/DSS mice

WT (n=8)

PAK1-/- (n=13)

WT + 5-ASA (n=16)

PAK1-/- + 5-ASA (n=13)

Dammann et al. Cancer Prev Res. 2015.

PAK1 deletion in AOM/DSS mice

Dammann et al. Cancer Prev Res. 2015.

PAK1 deletion in AOM/DSS mice

Dammann et al. Cancer Prev Res. 2015.

PAK1 inhibition impairs tumorigenesis

Dammann et al. Cancer Prev Res. 2015.

Conclusion

• PAK1 overexpression and activation in IBD likely drives tumorigenesis – Proliferation-> AKT-β-catenin

• PAK1 deletion impairs tumor-initiation in APCmin and AOM/DSS mice– Downregulation of AKT-β-catenin signaling

• 5-ASA’s chemopreventive effects likely mediate a PAK1-AKT-β-catenin axis

Thank you

• Supervisor: Univ. Prof. Dr. Christoph Gasche• Co-supervisor: Dr. Vineeta Khare• Colleagues and friends– Mag. Michaela Lang– Dr. Kristine Jimenez– Dr. Rayko Evstatiev– Felix Harpain– Dr. Adrian Frick– Tina Austerlitz– Max Baumgartner