Role of PLEXIND1/TGFβ signaling axis in pancreatic ductal adenocarcinoma progression correlates with the mutational status of KRAS

Vivekanandhan, S. et al. (2021) Role of PLEXIND1/TGFβ signaling axis in pancreatic ductal adenocarcinoma progression correlates with the mutational status of KRAS. Cancers, 13(16), 4048. (doi: 10.3390/cancers13164048)

Abstract

PLEXIND1 is upregulated in several cancers, including pancreatic ductal adenocarcinoma (PDAC). It is an established mediator of semaphorin signaling, and neuropilins are its known coreceptors. Herein, we report data to support the proposal that PLEXIND1 acts as a transforming growth factor beta (TGFβ) coreceptor, modulating cell growth through SMAD3 signaling. Our findings demonstrate that PLEXIND1 plays a pro-tumorigenic role in PDAC cells with oncogenic KRAS (KRASmut). We show in KRASmut PDAC cell lines (PANC-1, AsPC-1,4535) PLEXIND1 downregulation results in decreased cell viability (in vitro) and reduced tumor growth (in vivo). Conversely, PLEXIND1 acts as a tumor suppressor in the PDAC cell line (BxPC-3) with wild-type KRAS (KRASwt), as its reduced expression results in higher cell viability (in-vitro) and tumor growth (in vivo). Additionally, we demonstrate that PLEXIND1-mediated interactions can be selectively disrupted using a peptide based on its C-terminal sequence (a PDZ domain-binding motif), an outcome that may possess significant therapeutic implications. To our knowledge, this is the first report showing that (1) PLEXIND1 acts as a TGFβ coreceptor and mediates SMAD3 signaling, and (2) differential roles of PLEXIND1 in PDAC cell lines correlate with KRASmut and KRASwt status.

• Item Type: Articles
• Additional Information: This work is supported by the National Institutes of Health grants CA78383 (D. Mukhopadhyay) and CA150190 (D. Mukhopadhyay, M. Spaller).
• Keywords: Pancreatic ductal adenocarcinoma, PLEXIND1, KRAS, TGFβ, SMAD.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Chang, Professor David and Upstill-Goddard, Dr Rosie
• Authors: Vivekanandhan, S., Madamsetty, V. S., Angom, R. S., Dutta, S. K., Wang, E., Caulfield, T., Pletnev, A. A., Upstill-Goddard, R., Asmann, Y. W., Chang, D., Spaller, M. R., and Mukhopadhyay, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• ISSN (Online): 2072-6694
• Published Online: 11 August 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cancers 13(16): 4048
• Publisher Policy: Reproduced under a Creative Commons License