The Aurora-A-Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma.
We uncovered a crucial role for the Aurora kinase A (AURKA)-Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation - AURKA inhibits its ubiquitylation, increases its transcriptional activity and favors its homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop. Ablation of either AURKA or Twist1 completely inhibits EMT, highlighting both proteins as central players in EMT progression. Phosphorylation-dead Twist1 serves as a dominant-negative and fully reverses the EMT phenotype induced by Twist1, underscoring the crucial role of AURKA-mediated phosphorylation in mediating Twist1-induced malignancy. Likewise, Twist1-overexpressing BxPC3 cells formed large tumorsin vivo, whereas expression of phosphorylation-dead Twist1 fully abrogated this effect. Furthermore, immunohistochemical analysis of pancreatic cancer specimens revealed a 3-fold higher level of Twist1 compared to that seen in healthy normal tissues. This is the first study that links Twist1 in a feedback loop with its activating kinase, which indicates that concurrent inhibition of AURKA and Twist1 will be synergistic in inhibiting pancreatic tumorigenesis and metastasis.
Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA.
Jing
0000-0002-9066-514X
J
Wang
Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA.
Kumar
K
Nikhil
Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA.
Keith
K
Viccaro
Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA.
Lei
0000-0003-1062-9091
L
Chang
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, room A-128, Indianapolis, IN 46202, USA.
Max
M
Jacobsen
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, room A-128, Indianapolis, IN 46202, USA.
George
G
Sandusky
Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA shah23@purdue.edu.
Kavita
0000-0002-0451-1305
K
Shah
D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D055503:Protein Multimerization; D055550:Protein Stability; D021381:Protein Transport; D059748:Proteolysis; D013347:Subcellular Fractions / Q000378:metabolism; D013379:Substrate Specificity; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D064096:Aurora Kinase A
AURKA; Drug discovery; EMT; Pancreatic cancer; Therapy; Twist1