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Published on: August 23, 2019
A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice
B Weisz1, K Giehl, M Gana-Weisz
1Department of Neurobiochemistry, The George S Wise Faculty of Life Sciences, Tel-Aviv University, Israel.
Abstract:
Constitutively active Ras proteins, their regulatory components, and overexpressed tyrosine kinase receptors that activate Ras, are frequently associated with cell transformation in human tumors. This suggests that functional Ras antagonists may have anti-tumor activity. Studies in rodent fibroblasts have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts as a rather specific nontoxic Ras antagonist, dislodging Ras from its membrane anchorage domains and accelerating its degradation. FTS is not a farnesyltransferase inhibitor, and does not affect Ras maturation. Here we demonstrate that FTS also acts as a functional Ras antagonist in human pancreatic cell lines that express activated K-Ras (Panc-1 and MiaPaCa-2). In Panc-1 cells, FTS at a concentration of 25-100 microM reduced the amount of Ras in a dose-dependent manner and interfered with serum-dependent and epidermal growth factor-stimulated ERK activation, thus inhibiting both anchorage-dependent and anchorage-independent growth of Panc-1 cells in vitro. FTS also inhibited tumor growth in Panc-1 xenografted nude mice, apparently without systemic toxicity. Daily FTS treatment (5 mg/kg intraperitoneally) in mice with tumors (mean volume 0.07 cm3) markedly decreased tumor growth (after treatment for 18 days, tumor volume had increased by only 23+/-30-fold in the FTS-treated group and by 127+/-66-fold in controls). These findings suggest that FTS represents a new class of functional Ras antagonists with potential therapeutic value.
Insights
S-trans, transfarnesylthiosalicylic acid (FTS) dislodges Ras proteins from cell membranes, inhibiting tumor growth. This novel Ras antagonist shows potential as an anti-cancer therapy with minimal toxicity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ras proteins are frequently activated in human tumors, driving cell transformation.
- Targeting Ras signaling pathways is a promising strategy for cancer therapy.
- S-trans, transfarnesylthiosalicylic acid (FTS) is a known Ras antagonist in rodent cells.
Purpose of the Study:
- To investigate the efficacy of FTS as a functional Ras antagonist in human pancreatic cancer cells.
- To evaluate the anti-tumor activity and toxicity of FTS in preclinical models.
Main Methods:
- Human pancreatic cell lines (Panc-1, MiaPaCa-2) with activated K-Ras were treated with FTS.
- Ras protein levels and ERK activation were assessed.
- In vitro cell growth (anchorage-dependent and -independent) was measured.
- Tumor growth was evaluated in Panc-1 xenografted nude mice.
Main Results:
- FTS reduced Ras levels and inhibited ERK activation in human pancreatic cancer cells.
- FTS dose-dependently inhibited both anchorage-dependent and -independent growth in vitro.
- FTS significantly suppressed tumor growth in vivo with no apparent systemic toxicity.
Conclusions:
- FTS functions as a Ras antagonist in human pancreatic cancer cells.
- FTS demonstrates significant anti-tumor activity and a favorable safety profile in preclinical studies.
- FTS represents a potential new therapeutic agent for cancers driven by Ras.
