Ack1 tyrosine kinase activation correlates with pancreatic cancer progression.
Pancreatic cancer is a significant cause of cancer mortality worldwide as the disease has advanced significantly in patients before symptoms are evident. The signal transduction pathways that promote this rapid progression are not well understood. Ack1 or TNK2, an ubiquitously expressed oncogenic non-receptor tyrosine kinase, integrates signals from ligand-activated receptor tyrosine kinases to modulate intracellular signaling cascades. In the present study, we investigated the Ack1 activation profile in a pancreatic cancer tumor microarray, and observed that expression levels of activated Ack1 and pTyr284-Ack1 positively correlated with the severity of disease progression and inversely correlated with the survival of patients with pancreatic cancer. To explore the mechanisms by which Ack1 promotes tumor progression, we investigated the role of AKT/PKB, an oncogene and Ack1-interacting protein. Ack1 activates AKT directly in pancreatic and other cancer cell lines by phosphorylating AKT at Tyr176 to promote cell survival. In addition, the Ack1 inhibitor AIM-100 not only inhibited Ack1 activation but also suppressed AKT tyrosine phosphorylation, leading to cell cycle arrest in the G1 phase. This effect resulted in a significant decrease in the proliferation of pancreatic cancer cells and induction of apoptosis. Collectively, our data indicate that activated Ack1 could be a prognostic marker for ascertaining early or advanced pancreatic cancer. Thus, Ack1 inhibitors hold promise for therapeutic intervention to inhibit pancreatic tumor growth.
Department of Drug Discovery, Moffitt Cancer Center, Tampa, Florida 33612, USA.
Kiran
K
Mahajan
Domenico
D
Coppola
Y Ann
YA
Chen
Weiwei
W
Zhu
Harshani R
HR
Lawrence
Nicholas J
NJ
Lawrence
Nupam P
NP
Mahajan
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation; D006801:Humans; D053208:Kaplan-Meier Estimate; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D051057:Proto-Oncogene Proteins c-akt