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Resistance of human squamous carcinoma cells to transforming growth factor beta 1 is a recessive trait
M Reiss1, T Muñoz-Antonia, J M Cowan
1Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
Abstract:
Because most human squamous carcinoma cell lines of the aerodigestive and genital tracts are refractory to the antiproliferative action of transforming growth factor beta 1 (TGF beta 1) in vitro, we have begun to identify the causes for resistance of squamous carcinoma cell lines to TGF beta 1 by using somatic cell genetics. Two stable hybrid cell lines (FaDu-HKc.1 and FaDu-HKc.2) were obtained by fusing a TGF beta 1-resistant human squamous carcinoma cell line, FaDu-HygR, with a human papilloma virus 16-immortalized, TGF beta 1-sensitive, human foreskin keratinocyte cell line, HKc-neoR. Whereas TGF beta 1 did not inhibit DNA synthesis in parental FaDu-HygR cells, it reduced DNA synthetic activity of HKc-neoR, FaDu-HKc.1, and FaDu-HKc.2 cells by 75-85% (IC50, 2-5 pM). Although squamous carcinoma cells express lower than normal levels of TGF beta 1 type II receptors on their cell surface, TGF beta 1 type II receptor mRNA was detected in all four cell lines. Recessive genes involved in TGF beta 1 signaling may be localized to the distal portion of chromosome 18q, as this was the sole chromosomal region of homozygous deletion in parental FaDu-HygR cells. Furthermore, our previous observation that mutant p53 decreases sensitivity of keratinocytes to TGF beta 1 was supported by the finding that the level of the mutant p53 protein expressed by the hybrid cell lines was greatly reduced. In summary, TGF beta 1 resistance of FaDu cells appears to be recessive and is presumably due to the loss of one or more post-receptor elements of the signaling pathway.
Insights
Squamous cell carcinoma resistance to transforming growth factor beta 1 (TGF-β1) is recessive, likely due to defects in post-receptor signaling. This study used somatic cell genetics to identify factors contributing to TGF-β1 resistance in cancer cells.
Area of Science:
- Oncology
- Cell Biology
- Genetics
Background:
- Most human squamous cell carcinoma lines are resistant to the antiproliferative effects of transforming growth factor beta 1 (TGF-β1).
- Understanding the mechanisms of TGF-β1 resistance is crucial for developing effective cancer therapies.
Purpose of the Study:
- To identify the genetic basis of resistance to TGF-β1 in human squamous carcinoma cell lines using somatic cell genetics.
- To investigate the role of TGF-β1 signaling pathway components in cancer cell resistance.
Main Methods:
- Fusing a TGF-β1-resistant squamous carcinoma cell line (FaDu-HygR) with a TGF-β1-sensitive keratinocyte cell line (HKc-neoR) to create hybrid cell lines.
- Assessing the antiproliferative response to TGF-β1 in parental and hybrid cell lines.
- Analyzing TGF-β1 type II receptor expression and chromosomal deletions.
Main Results:
- Hybrid cell lines (FaDu-HKc.1 and FaDu-HKc.2) regained sensitivity to TGF-β1, indicating recessive resistance mechanisms.
- TGF-β1 significantly inhibited DNA synthesis in sensitive cell lines and hybrids.
- Homozygous deletion in chromosome 18q of the resistant parental cell line suggests localization of key TGF-β1 signaling genes.
- Reduced levels of mutant p53 protein in hybrid cells correlated with increased TGF-β1 sensitivity.
Conclusions:
- TGF-β1 resistance in FaDu squamous carcinoma cells is a recessive trait.
- The resistance is likely caused by defects in post-receptor elements of the TGF-β1 signaling pathway.
- Chromosome 18q and potentially mutant p53 are implicated in TGF-β1 resistance mechanisms.