Silencing of Neuropilins and GIPC1 in pancreatic ductal adenocarcinoma exerts multiple cellular and molecular antitumor effects

Hannes Borchardt, Alexander Schulz, Kaustubh Datta, Michael H. Muders, Achim Aigner

Research output: Contribution to journalArticle

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality, with new treatment options urgently needed. Neuropilins-1/-2 (NRP1, NRP2) are receptors for semaphorins and angiogenic growth factors, while the GAIP interacting protein C-terminus 1 (GIPC1, aka Synectin) interacts with the neuropilins. They are overexpressed in PDAC and associated with poor survival as well as tumor-promoting activities. Thus, neuropilin and/or GIPC1 silencing may inhibit PDAC growth. In this study, we directly compare the various tumor-inhibitory effects of transient RNAi-mediated depletion of NRP1, NRP2 and GIPC1, alone or in combination, in a set of cell lines with different expression levels. Inhibition of anchorage-dependent and –independent proliferation, colony formation and cell migration, alterations of 3D-spheroid size and shape as well as retardation of cell cycle and induction of apoptosis have been analyzed and found to vary between cell lines. The observed effects are independent of initial expression levels. Knocking down NRP1, NRP2, and GIPC1 alone demonstrates significant effects. Only small additive effects upon combined knockdown and no counter-upregulation of the respective other genes could be detected. Making the study more translational, we show that systemic treatment of PDAC xenograft-bearing mice with polymeric nanoparticles for delivery of specific siRNAs results in tumor inhibition, reduces proliferation, and induces apoptosis. In conclusion, NRP and GIPC1 inhibition emerges as a promising avenue in PDAC treatment due to pleiotropic tumor-inhibitory effects.

Original languageEnglish (US)
Article number15471
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Neuropilins
Adenocarcinoma
Neuropilin-2
Neuropilin-1
Semaphorins
Apoptosis
Cell Line
Neoplasms
Angiogenesis Inducing Agents
RNA Interference
Protein C
Heterografts
Nanoparticles
Cell Movement
Intercellular Signaling Peptides and Proteins
Cell Cycle
Up-Regulation
Mortality
Growth

ASJC Scopus subject areas

  • General

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Silencing of Neuropilins and GIPC1 in pancreatic ductal adenocarcinoma exerts multiple cellular and molecular antitumor effects. / Borchardt, Hannes; Schulz, Alexander; Datta, Kaustubh; Muders, Michael H.; Aigner, Achim.

In: Scientific reports, Vol. 9, No. 1, 15471, 01.12.2019.

Research output: Contribution to journalArticle

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