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Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and

Ferenc Sipos1, Bettina Bohusné Barta1, Ágnes Simon1

  • 1Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary.

Pathology Oncology Research : POR
|June 2, 2022
PubMed

Insights

In HT29 colon cancer cells, inhibiting Insulin-like Growth Factor 1 Receptor (IGF1R) with self-DNA showed anti-proliferative effects, modulated by Toll-like Receptor 9 (TLR9) signaling. Autophagy influenced survival of stem-like cancer cells.

Area of Science:

  • Oncology
  • Cell Biology
  • Immunology

Background:

  • A complex interplay exists between self-DNA-induced Toll-like Receptor 9 (TLR9) signaling and autophagy in HT29 colon cancer cells, impacting cell survival and differentiation.
  • Insulin-like Growth Factor 1 Receptor (IGF1R) activation is implicated in colorectal cancer progression, yet its effect on autophagy remains controversial.
  • The specific roles of IGF1R inhibition in conjunction with TLR9 and autophagy signaling within HT29 cancer cells require further elucidation.

Purpose of the Study:

  • To investigate the intricate interactions between IGF1R inhibition and TLR9/autophagy signaling pathways in HT29 colon cancer cells.
  • To clarify the dual role of autophagy in response to combined IGF1R inhibition, TLR9 activation, and self-DNA exposure.

Main Methods:

  • HT29 cells were treated with tumor-derived self-DNA and inhibitors of IGF1R (picropodophyllin), autophagy (chloroquine), and TLR9 (ODN2088).
  • Assays included cell proliferation, metabolic activity, cell counting, gene expression analysis (NanoString, Taqman), immunocytochemistry, Western blot, and transmission electron microscopy.

Main Results:

  • Combined treatment with self-DNA and IGF1R inhibitors demonstrated anti-proliferative effects, which were reversed by TLR9 inhibition.
  • Autophagy modulation by picropodophyllin, ODN2088, and chloroquine had varied effects on HT29 cell proliferation, indicating a "Janus-faced" role.
  • Induced autophagy did not prevent HT29 cell death but promoted the survival of CD133-positive stem-like cells.

Conclusions:

  • Targeting IGF1R in combination with TLR9 and/or autophagy signaling presents a promising strategy for developing personalized anti-tumor therapies for colorectal cancer.
  • Further research into combined inhibition strategies could lead to more effective treatments for colorectal cancer, particularly for stem-like cancer cell populations.
Keywords:
CD133HT29 cancer cellIGF1RTLR9autophagyself-DNA

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