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This study investigates the role of extracellular PKM2 in tissue regeneration and wound healing. The findings suggest that PKM2 interacts with integrins avb3 to promote angiogenesis and fibroblast cell migration, facilitating the wound healing process. This research has potential implications for the development of diagnostic and therapeutic agents for cancer progression.
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Extracellular PKM2 – Promotes Wound Healing Zhi-Ren Liu Department of Biology, GSU
Research Directions Functional roles of p68 RNA helicase in cancer progression and metastasis Tumor bio-energetic, role of PKM2 in cancer progression Extracellular PKM2 in tissue regeneration Development of Diagnostic and therapeutic agents by protein engineering (Joint projects with Jenny Yang)
PKM2 in Glucose Metabolism in Cancer Cells Pentose phosphate pathway PKM2 NADPH+ribose-5-Pi Warburg Effect Cancer cells use glycolysis even in the presence of oxygen
PKM2 Is a Protein Kinase in Gene Expressions Glucose G-6-P Pentose Phosphate Pathway NADPH, R5P Glycolysis PEP Growth signals PKM2 active Pyruvate P Stat3 RNA Pol II MEK5 inactive Gao, X, et.al. Mol.Cel., 2012
Extracellular PKM2, A Diagnostic/Prognostic Marker PKM2 levels in blood circulation or stool are diagnosis/prognosis marker How Does PKM2 released to blood circulation? Does circulative PKM2 have any functional role in cancer progression? Thousands Refs
Extracellular PKM2 Promotes Tumor Angiogenesis Glucose G-6-P Pentose Phosphate Pathway NADPH, R5P Glycolysis PEP Growth signals PKM2 active Pyruvate P Stat3 RNA Pol II MEK5 inactive Stroma Cells Endothelial Cells Cancer Cells Angiogenesis, Metastasis, & drug resistance
Wound Healing Processes 1. Hemostasis 2. Inflammation . 3. Proliferation 4. Maturation
Extracellular rPKM2 Promotes Angiogenesis at Wound Site Green: CD31 Stains
Age Effects Mouse Age 9 -10 weeks Mouse Age 5 weeks rPKM2 ProWoud rPKM2 rPKM1 Control rPKM1 Buffer Buffer % of healing Day3 Day6 Day9 Day3 Day6 Day9 Day0 Day0
Extracellular PKM2 is released to the wound site by an intrinsic mechanism IHC via a-PKM2
PKM2 Released by Nutrophils at Wound Site PKM2 Neutrophils Day 4 Day 1 Day 3 No wound Day 2
PKM2 Released by Nutrophils at Wound Site Neutrophils isolated from mouse blood IHC of wound tissue sections Dam is activator for primary and 2nd neutrophil degranulation Beige-J mice have defects in neutrophil migration
rPKM2 Promotes Granulation at Wound Buffer The PKM2 treatment group had much better wound healing. Granulations were clearly started early time. There were also obvious richer in vessels in the wound areas in the PKM2 treatment group. rPKM1 Granulations rPKM2
Extracellular PKM2 Promotes Fibroblast Cell Migration Green: Fibroblast Blue: DAPI HDFa Cells: Primary human dermal fibroblast cells
Extracellular PKM2 promotes myofibroblast differentiation Sections from wound tissue Green: a-SMA Blue: DAPI PKM1 PKM2 TGF-β HDFa cells HDFa cells Red: a-SMA Blue: DAPI
rPKM2 Promotes Wound Healing with Diabetic Mice Diabetic db/db mice at 15 weeks old rPKM2 and rPKM1 were used in 0.04% W/W in pharmacy cream and water in PBS rPKM2 day0 day3 day6 day9 Buffer % of healing rPKM1 rPKM1 rPKM2 Day 0 Day 3 Day 6 Day 9 % of healing = Initial wound areas - measured wound areas at a given day/initial wound areas The error bars are the standard deviations among the five mice.
Acknowledgments Collaborators: Dr. Jenny J. Yang Dept. of Chemistry Georgia State Univ. Dr. Shi-Yong Sun Winship Cancer Institute Emory University Dr. Z.G. Chen Winship Cancer Institute Emory University Dr. Xiao-Ping Hu Dr. Hui Mao Emory University Members of Dr. Yang’s laboratory, Dept. of Chem, GSU • National Institute of Health Ms. Birgit Neuhaus • American Heart Association Dept. of Biology GSU. Dr. Shiming Wang • Georgia Cancer Coalition Dept. of Chemistry GSU. • MBD pre-doctoral fellowship.
