Abstract 943: Retinoid sensitizes Tumor Necrosis Factor (TNF) -related apoptosis inducing ligand -induced cytotoxic effect in breast cancer by upregulating cell surface receptor Death Receptor-4 expression
Authors: Kratz Annekatrine , Zang Chuanbing , Eucker Jan , Liu Hongyu 
Published: July 2016

Abstract
Tumor Necrosis Factor (TNF) -related apoptosis inducing ligand (TRAIL, also called APO-2L) is a member of the TNF super family which is known to induce apoptosis selectively in tumor cells, whereas its cytotoxicity to non-transformed cells turned out as low to moderate. The potential of TRAIL as a pharmacotherapeutic agent against cancer is therefore widely pre-clinically and clinically investigated. However, the test results from a wide range of in vitro models revealed that a great portion of tumor cell cultures displayed inherent or acquired resistances towards TRAIL-mediated cell death. Mechanisms underlying these resistances comprise, among others, downregulation of cell surface receptors of TRAIL, namely Death Receptors (e.g. DR4, DR5). Hence, enhancing the DRs expression by application of TRAIL in combination with other therapeutics, is one of the diverse approaches to augment the TRAIL-sensitivity and overcome the resistance.
The term Retinoids comprises different polyisoprenoids of the Vitamin-A-group. The derivatives all-trans- and 9-cis retinoic acid (ATRA and 9-cis-RA) function as activators of transcription initiating nuclear hormone receptors and hereby regulate key components of carcinogenesis like proliferation, differentiation and apoptosis. Furthermore, Retinoids have proven potential in the secondary prevention of breast cancer. In this study, we investigated whether the combination of TRAIL with Retinoids could be a new therapeutic approach for breast cancer treatment. Our results indicate that simultaneous incubation with TRAIL and ATRA resulted in a synergistic inhibition of proliferation in the Retinoids-sensitive breast cancer cells. This synergistic combination effect on cell proliferation correlated with augmented cell apoptosis as detected with different methods. Immunoblotting assays revealed that the apoptosis-regulaing factors for both intrinsic and extrinsic apoptotic pathways including Bcl-2 family members, Bid, survivin, and diverse caspases were involved in the combination treatment-triggered apoptosis folowing the Apo2L/TRAIL activation. Analysis of cell surface DRs expression by flow cytometry demonstrated that ATRA contributed to the enhancement of TRAIL-sensitivity most possibly by increasing the TRAIL receptor DR4 but not DR5 expression and thus leading to more strong apoptotic effect when cells were upon TRAIL treatment.
Taken together, we demonstrated for first time that Retinoid derivatives can be used to enhance the cytotoxic effect of TRAIL in some sub-entities of breast cancer by upregulating the DR4 cell surface expression. Our study provides a rationale for future clinical trials.
Citation Format: Annekatrine Kratz, Chuanbing Zang, Jan Eucker, Hongyu Liu. Retinoid sensitizes Tumor Necrosis Factor (TNF) -related apoptosis inducing ligand -induced cytotoxic effect in breast cancer by upregulating cell surface receptor Death Receptor-4 expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 943.