TRAIL mediates apoptosis in cancerous but not normal primary cultured cells of the human reproductive tract

Abstract

Cancer of the reproductive tract encompasses malignancies of the uterine corpus, cervix, ovary, Fallopian tube, among others and accounts for 15% of female cancer mortalities. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates apoptosis by binding to death receptors and offers a promising cancer treatment. The goal of this study was to investigate and characterize the effect of TRAIL in endometrial cancer cell lines and normal (non-cancerous) epithelial cells of endometrial origin. We also examined the effect of TRAIL in other primary cultured cancers and normal cells of the human female reproductive tract and evaluated if TRAIL mediated apoptosis correlated with death receptors and decoy receptors 1 and 2.Herein, we demonstrate that TRAIL at concentrations which kill cancerous cells, does not mediate apoptosis or alter cell viability in normal human endometrium, ovary, cervix or Fallopian tube. The partial inhibition by a caspase 9 inhibitor and the total inhibition by a caspase 8 inhibitor demonstrates the dependency on the extrinsic apoptotic pathway. The selective mortality does not correlate with the presence of death or decoy receptors. These results suggest that TRAIL may be an effective treatment for endometrial cancer and other female reproductive cancers, with minimal secondary effects on healthy tissue.

Lipophilic but not hydrophilic statins selectively induce cell death in gynecological cancers expressing high levels of HMGCoA reductase.

“…Primary cultures of human tissues were established following protocols previously published by our group [27]. Normal ovarian culture, the ovarian tissue was washed with HBSS medium (Hank’s Balanced Salt Solution) without calcium, magnesium or phenol red (Invitrogen, NY, USA), supplement with antibiotics (penicillin 100 U/ml, streptomycin 100 ug/ml) (Invitrogen).…”

“…Cell viability was assessed by the MTS (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye reduction assay as described previously [27]. All experiments were performed in quintuplicate and repeated at least three times.…”

Knockdown of MTDH Sensitizes Endometrial Cancer Cells to Cell Death Induction by Death Receptor Ligand TRAIL and HDAC Inhibitor LBH589 Co-Treatment

“…Tumor necrosis factor (TNF)-α-related apoptosis-inducing ligand (TRAIL) recently emerged as a promising targeted therapeutic strategy in various types of cancers due to its pro-apoptotic characteristics [12], [13]. As a member of the TNF family, TRAIL specifically activates extrinsic apoptotic pathways in cancer cells by binding to death receptors.…”

“…As a member of the TNF family, TRAIL specifically activates extrinsic apoptotic pathways in cancer cells by binding to death receptors. Importantly, TRAIL selectively promotes apoptosis of tumor cells but has no effect on normal human reproductive tract cells including those in the endometrium, ovary, cervix, or fallopian tube [13]. Some cancer cells are resistant to TRAIL-induced apoptosis [14], [15], [16], therefore combinatorial regimens have been adopted to restore sensitivity [13], [17].…”

“…Importantly, TRAIL selectively promotes apoptosis of tumor cells but has no effect on normal human reproductive tract cells including those in the endometrium, ovary, cervix, or fallopian tube [13]. Some cancer cells are resistant to TRAIL-induced apoptosis [14], [15], [16], therefore combinatorial regimens have been adopted to restore sensitivity [13], [17]. In several studies, histone deacetylase (HDAC) inhibitors have been demonstrated to further increase sensitivity to TRAIL-induced apoptotic cell death [18], [19], [20], [21].…”