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Poster Display session 1

1657 - Modulation of TLR9-dependent autophagy response via inhibition of c-Met signaling influences the survival of HT29 cancer cells

Date

28 Sep 2019

Session

Poster Display session 1

Topics

Pathology/Molecular Biology

Tumour Site

Presenters

Ferenc Sipos

Citation

Annals of Oncology (2019) 30 (suppl_5): v797-v815. 10.1093/annonc/mdz269

Authors

F.J. Sipos1, L. Nagy1, B. Barta1, Á. Simon1, T. Dankó2, A. Sebestyén2, A.L. Kiss3, G. Műzes1

Author affiliations

  • 1 Division Of Immunology, Semmelweis University, 2nd Dept. of Internal Medicine, 1088 - Budapest/HU
  • 2 Biology, 1st Department of Pathology and Experimental Cancer Research, 1085 - Budapest/HU
  • 3 Department Of Human Morphology And Developmental Biology, Semmelweis University, 1085 - Budapest/HU

Resources

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Abstract 1657

Background

In HT29 cells, an interplay between self-DNA-induced TLR9- and autophagy responses was found with remarkable effects on survival and differentiation of tumor cells. c-Met activation is known to drive the progression of colorectal cancer by promoting signaling cascades that mainly result in alterations of cell motility, survival and proliferation. c-Met inhibition was shown to inhibit autophagy. In cancer cells the interrelated role of c-Met inhibition and TLR9/autophagy signaling has not yet been clarified, so we aimed to assess this complex interplay.

Methods

HT29 cells were incubated for 72 h with genomic (g), hypermethylated (m), and fragmented (f) tumor self-DNAs, and with/without inhibitors of c-Met (diisothiocyanatostilbene), autophagy (chloroquine) and TLR9 (ODN2088), respectively. Cell viability was measured by MTT assay. Transcriptional changes of TLR9-signaling, PI3K, CD95, c-Met, Bcl2, cytochrome-c, and the autophagy process were assayed by Human v3 miRNA Assay (NanoString). Autophagy proteins were detected by immunocytochemistry, while morphology of apoptosis and autophagy by transmission electron microscopy (TEM).

Results

Self-DNAs g and f resulted in significant upregulation of Beclin1, Atg16L1, LC3 mRNAs, and downregulation of PI3K, Bcl2, CD95, and cytochrome-c, verified by immunocytochemistry, as well. c-Met inhibition alone altered inversely the autophagy-associated gene- and protein-expressions. In each group of tumor cells using combined inhibition of autophagy, TLR9 and/or c-Met-signaling varying degree of autophagy was observed according to NanoString and TEM. Following combined incubation with c-Met inhibitor and m-DNAs no expected suppression of tumor cell survival and induction of apoptosis and mitophagy were detected. Further, c-Met inhibition changed the cell-protective effect f-DNA on macroautophagy.

Conclusions

Our study provided evidence for an intense crosstalk between the inhibited c-Met canonical and non-canonical signaling pathways, and the TLR9/autophagy response with profound impacts on survival, proliferation and death of HT29 cells subjected to intact/modified self-DNAs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Ferenc Sipos.

Funding

StartUp.

Disclosure

All authors have declared no conflicts of interest.

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