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Inhibition by retinoic acid of murine retrovirus-induced cellular transformation and tumor formation
Abstract:
The effect of all-trans-retinoic acid (RA) on cellular transformation and on tumorigenicity of retrovirally transformed cells was investigated. RA treatment of NRK and NIH/3T3 cells transformed by BALB/c murine sarcoma virus (MuSV), Kirsten murine sarcoma virus (K-MuSV), and simian sarcoma virus resulted in a significant reduction in anchorage-dependent growth of only K-MuSV-transformed NRK cells. A 62% reduction in cell number was observed at 10(-5) M RA. In contrast, anchorage-independent growth induced by each of the viruses tested was suppressed by RA. Balb/cMSV3T3 cells showed the greatest level of sensitivity with a significant reduction in anchorage-independent growth occurring at 10(-9) M RA. The level of cytoplasmic retinoic acid-binding protein (CRABP) was determined in both parent and transformed cell lines. CRABP was present at a high level in all 3T3 cell types but was absent in all NRK cell lines. For testing the antineoplastic activity of RA in vivo, Balb/cMSV3T3 cells were injected intradermally into nude mice. Subsequent treatment of the tumor sites of these animals by topical application of RA resulted in a significant reduction in both tumor incidence and tumor size, confirming the in vitro results. Analysis of the level of v-onc mRNA revealed that inhibition of retroviral transformation by RA was not due to a decrease in transcription of the v-onc genes.
Insights
All-trans-retinoic acid (RA) suppresses anchorage-independent growth in retrovirally transformed cells and reduces tumor formation in vivo. This anti-cancer effect is independent of v-onc gene transcription levels.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Retroviral transformation of cells can lead to cancer.
- All-trans-retinoic acid (RA) is a derivative of vitamin A with potential anti-cancer properties.
- Understanding RA's effect on cellular transformation and tumorigenicity is crucial for developing new cancer therapies.
Purpose of the Study:
- To investigate the effect of all-trans-retinoic acid (RA) on cellular transformation and tumorigenicity.
- To determine the sensitivity of different retrovirally transformed cell lines to RA.
- To explore the role of cytoplasmic retinoic acid-binding protein (CRABP) in RA's effects.
Main Methods:
- Treatment of NRK and NIH/3T3 cells transformed by various sarcoma viruses with RA.
- Assessment of anchorage-dependent and anchorage-independent cell growth.
- Quantification of cytoplasmic retinoic acid-binding protein (CRABP) levels.
- In vivo studies involving tumor induction in nude mice and topical RA treatment.
Main Results:
- RA significantly reduced anchorage-independent growth in all tested retrovirally transformed cell lines, with Balb/cMSV3T3 cells being highly sensitive.
- Topical RA application in vivo significantly reduced tumor incidence and size in mice bearing Balb/cMSV3T3 tumors.
- CRABP was present in 3T3 cell lines but absent in NRK cell lines, suggesting a potential role in differential sensitivity.
- RA's inhibitory effect was not linked to decreased v-onc gene transcription.
Conclusions:
- All-trans-retinoic acid (RA) demonstrates potent anti-tumorigenic activity against retrovirally transformed cells both in vitro and in vivo.
- RA effectively suppresses anchorage-independent growth, a key characteristic of transformed cells.
- The mechanism of RA's action does not involve downregulation of viral oncogene expression.