title: Coupling G2/M arrest to the Wnt/β-catenin pathway restrains pancreatic adenocarcinoma.
abstract: β-catenin plays a pivotal role in organogenesis and oncogenesis. Alterations in β-catenin expression are common in pancreatic cancer, which is an extremely aggressive malignancy with a notably poor prognosis. In this report, we analyzed the apoptotic activity of withanolide-D (witha-D), a steroidal lactone that was purified from an Indian medicinal plant, Withania somnifera, and its underlying mechanism of action. Witha-D induced apoptosis in pancreatic ductal adenocarcinoma cells by prompting cell-cycle arrest at the G2/M phase. This lactone abrogated β-catenin signaling in these cells regardless of disease grade, mutational status, and gemcitabine sensitivity. Witha-D also upregulated E-cadherin in most cells, thereby supporting the inversion of the epithelial-mesenchymal transition. Furthermore, the Akt/Gsk3β kinase cascade was identified as a critical mediator of G2/M regulation and β-catenin signaling. Witha-D deactivated Akt, which failed to promote Gsk3β deactivation phosphorylation. Consequently, activated Gsk3β facilitated β-catenin destruction in pancreatic carcinoma cells. The knockdown of Chk1 and Chk2 further activated Akt and reversed the molecular signal. Taken together, the results of the current study represent the first evidence of β-catenin signal crosstalk during the G2/M phase by functionally inactivating Akt via witha-D treatment in pancreatic cancer cells. In conclusion, this finding suggests the potential identification of a new lead molecule in the treatment of pancreatic adenocarcinoma.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4, Raja S.C. Mallick Road, Kolkata 700032, West Bengal, India Bio-Processing Unit, Department of Bio-Technology, Govt. of India, Mohali, Punjab, India.
authors.forename: Sayantani
authors.initials: S
authors.lastname: Sarkar
authors.forename: Chandan
authors.initials: C
authors.lastname: Mandal
authors.forename: Rajender
authors.initials: R
authors.lastname: Sangwan
authors.forename: Chitra
authors.initials: C
authors.lastname: Mandal
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054358:Withanolides / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; D054358:Withanolides; D051176:beta Catenin; C010376:withanolide D; D012313:RNA; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Chk1/Chk2; EMT; G2/M; Wnt signaling; pancreatic adenocarcinoma; β-catenin