Dual role of Par‐4 in abrogation of EMT and switching on Mesenchymal to Epithelial Transition (MET) in metastatic pancreatic cancer cells. Issue 9 (15th May 2018)

• Record Type: Journal Article
• Authors: Katoch, Archana; Suklabaidya, Sujit; Chakraborty, Souneek; Nayak, Debasis; Rasool, Reyaz U.; Sharma, Deepak; Mukherjee, Debaraj; Faheem, Mir M.; Kumar, Anmol; Sharma, Parduman R.; Senapati, Shantibhusan; Kumar, Lekha D.; Goswami, Anindya
• Is Part Of: Molecular carcinogenesis. Volume 57:Issue 9(2018)
• Page Start: 1102
• Page End: 1115
• Publication Date: 2018-05-15
• Subjects: ALK2 -- mesenchymal‐epithelial transition -- metastasis -- NGD16 -- Par‐4 -- Smad4; Carcinogenesis -- Molecular aspects -- Periodicals; 616.994071
• DOI: 10.1002/mc.22828
• Languages: English
• ISSNs: 0899-1987

Abstract

Abstract : Epithelial‐mesenchymal transition (EMT) is a critical event that occurs during the invasion and metastatic spread of cancer cells. Here, we conceive a dual mechanism of Par‐4‐mediated inhibition of EMT and induction of MET in metastatic pancreatic cancer cells. First, we demonstrate that 1, 1′‐β‐D‐glucopyranosyl‐3, 3′‐bis(5‐bromoindolyl)‐octyl methane (NGD16), an N‐glycosylated derivative of medicinally important phytochemical 3, 3′‐diindolylmethane (DIM) abrogates EMT by inducing pro‐apoptotic protein Par‐4. Induction of Par‐4 (by NGD16 or ectopic overexpression) strongly impedes invasion with inhibition of major mesenchymal markers viz. Vimentin and Twist‐1 epithelial marker‐ E‐cadherin. Further, NGD16 triggers MET phenotypes in pancreatic cancer cells by augmenting ALK2/Smad4 signaling in a Par‐4‐dependent manner. Conversely, siRNA‐mediated silencing of endogenous Par‐4 unveil reversal of MET with diminished E‐cadherin expression and invasive phenotypes. Additionally, we demonstrate that intact Smad4 is essential for Par‐4‐mediated maintenance of E‐cadherin level in MET induced cells. Notably, we imply that Par‐4 induction regulates E‐cadherin levels in the pancreatic cancer cells via modulating Twist‐1 promoter activity. Finally, in vivo studies with syngenic mouse metastatic pancreatic cancer model reveal that NGD16 strongly suppresses metastatic burden, ascites formation, and prolongs the overall survival of animals effectively.