Growth inhibition in clonal subpopulations of a human epithelioid sarcoma cell line by retinoic acid and tumour necrosis factor alpha

Abstract

Epithelioid sarcoma is a highly malignant soft tissue tumour that is refractory to conventional chemotherapy and irradiation. Since permanent cell lines of this tumour are extremely rare, in vitro data on compounds with significant antiproliferative effects are still lacking. Therefore, we investigated the effects of retinoic acid (RA) and tumour necrosis factor alpha (TNF-alpha) on tumour cell proliferation of three different clonal subpopulations (GRU-1A, GRU-1B, GRU-1C) derived from the same human epithelioid sarcoma cell line, GRU-1. In GRU-1A both RA (P=0.01) and TNF-alpha (P=0.002) exhibited highly significant and dose-dependent growth inhibitory effects, which could further be increased by a combined application of both compounds (P<0.006). GRU-1B proved to be sensitive to RA (P=0.006), whereas no response to TNF-alpha was observed. GRU-1C was resistant to both RA and TNF-alpha. The antiproliferative effect of TNF-alpha was mediated by TNF receptor 1(TNF-R1) and correlated positively with both the number of TNF-R1 per cell and receptor affinity. No correlation was detected between RA-induced growth inhibition and the expression pattern of the RA receptors (RARs) RAR-alpha, RAR-beta, and RAR-gamma. Plating efficiency, however, could exclusively be reduced by RA in GRU-1B, the only cell line expressing RAR-alpha. Taken together, these data are the first showing significant antiproliferative effects in human epithelioid sarcoma by RA and TNF-alpha. Whereas the TNF-alpha response seems to depend on the expression of TNF-R1, no simple correlation could be found between RA sensitivity and the expression pattern of RARs. Images Figure 1 Figure 3

Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

“…As RAR-γ constitutes a universal receptor for the used retinoids (Repa et al, 1997;Fisher et al, 1998), a defect in the presence of a relevant receptor can be excluded as an explanation for our findings. Thus, no simple correlation of retinoid sensitivity with the expression pattern of RARs could be established for STS cell lines which is in accordance with previous reports (Van der Leede et al, 1993;Engers et al, 1996). Although p53-mutated HTB-92 and HTB-94 cell lines showed intensive nuclear staining by immunohistochemistry, the p53 mutated HTB-91 cell line showed no nuclear staining.…”

High levels of cellular retinol binding protein-1 expression in leiomyosarcoma: possible implications for diagnostic evaluation

“…RARα mediates RA effects in CRBP-1-expressing SMCs in vitro [29]. The role of RARα as nuclear transducer of retinoic effects appears tissue specific, since the correlation between RA-induced growth inhibition and changes of the expression of RA nuclear receptors differs in other neoplastic derived cell lines [15,18]. Similarly, DNA synthesis inhibition is observed in myometrial and stromal endometrial cells but not in adjacent epithelium [6].…”

“…It is well known that the efficacy of hormonal therapy for the treatment of breast cancer depends on the expression by neoplastic cells of steroid receptors [9]. In vitro retinoids inhibit proliferation and induce apoptosis in several soft tissue sarcoma cell lines [14,15,43]. Variable levels of CRBP-1 expression may also explain the different sensitivity of myogenic tumor cell lines to retinoid administration [14].…”

Paclitaxel (Taxol®)-induced apoptosis in human epithelioid sarcoma cell lines is enhanced by upregulation of CD95 ligand (FasL/Apo-1L)

“…To that end, we used the human ES cell line GRU-1 and its clonal subpopulations GRU-1A, -1B and -1C, which have previously been characterized with respect to their potential for multidirectional diVerentiation, invasiveness as well as their response to TNF-and retinoic acid (Engers et al 1996(Engers et al , 1994.…”