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Continuous treatment with FTS confers resistance to apoptosis and affects autophagy

Eran Schmukler1, Eya Wolfson1, Zvulun Elazar2

  • 1Department of Neurobiology. Tel-Aviv University, Ramat-Aviv, Israel.

Plos One
|February 3, 2017
PubMed

Insights

Prolonged treatment with FTS (Salirasib) induces drug resistance in colon cancer cells by altering autophagy and reducing apoptosis. These resistant cells show changes in Ras signaling pathways, impacting therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Ras proteins are frequently altered in human cancers, driving aggressive tumor growth.
  • Farnesylcysteine mimetic (FTS), or Salirasib, inhibits Ras and shows anti-tumorigenic effects.
  • Short-term FTS treatment can induce protective autophagy in cancer cells, but prolonged exposure may lead to drug resistance.

Purpose of the Study:

  • To investigate the effects of prolonged FTS treatment on drug resistance in HCT-116 human colon cancer cells.
  • To determine the role of autophagy in the development of FTS resistance.
  • To analyze changes in Ras-related signaling pathways and apoptosis in FTS-resistant cells.

Main Methods:

  • HCT-116 colon cancer cells were treated with FTS for 6 months to induce resistance.
  • Assessed FTS resistance by measuring cell growth inhibition and cell death.
  • Analyzed autophagy markers, apoptosis levels, and Ras-related signaling pathway alterations in resistant cells.
  • Examined p62 cleavage as an indicator of apoptosis.

Main Results:

  • Cells developed resistance to FTS-induced growth inhibition and cell death after 6 months of treatment.
  • FTS-resistant cells exhibited altered autophagy and reduced apoptosis compared to sensitive cells.
  • Changes in Ras-related signaling pathways were observed in FTS-resistant cells.
  • FTS-resistant cells showed decreased apoptosis and p62 cleavage following FTS treatment.

Conclusions:

  • Prolonged FTS treatment leads to acquired drug resistance in colon cancer cells.
  • Altered autophagy, reduced apoptosis, and modified Ras signaling are key mechanisms of FTS resistance.
  • Understanding these resistance mechanisms is crucial for developing more effective cancer therapies.

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