Katoch, A. et al. (2018) Dual role of Par-4 in abrogation of EMT and switching on mesenchymal to epithelial transition (MET) in metastatic pancreatic cancer cells. Molecular Carcinogenesis, 57(9), pp. 1102-1115. (doi: 10.1002/mc.22828) (PMID:29672923)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Katoch, Dr Archana |
| Authors: | Katoch, A., Suklabaidya, S., Chakraborty, S., Nayak, D., Rasool, R. U., Sharma, D., Mukherjee, D., Faheem, M. M., Kumar, A., Sharma, P. R., Senapati, S., Kumar, L. D., and Goswami, A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Molecular Carcinogenesis |
| Publisher: | Wiley |
| ISSN: | 0899-1987 |
| ISSN (Online): | 1098-2744 |
| Published Online: | 19 April 2018 |
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