Abstract 4890: Understanding the crosstalk between glycosylation and drug resistance

Abstract Although great progress has been made in the treatment of breast cancer, resistance to chemotherapeutic drugs is a problem facing current cancer research, promoting the need to understand the molecular mechanisms involved in breast cancer and identify future targeted therapy. One of the mechanisms by which chemoresistance is attained in cancer cells is mediated through the expression of MDR-related glycoproteins (MRPs). These transmembrane proteins efflux drugs across the plasma membrane, conferring resistance of cancer cells to anticancer drugs. Elevated expression of Multidrug Resistance Protein 1 (MRP1) has been associated with poor prognosis and survival rate among breast cancer patients. Acquiring drug resistance has been correlated to the emergence of metastasis, accounting for the progression of the disease. Altered cell-surface glycosylation is a common feature of cancer initiation and progression. During glycosylation, the MRP1 undergoes N-linked glycosylation but it is unclear how glycosylation impacts the drug transport activity. To examine the crosstalk between MRP1 and Neuraminidase 1 (Neu1), the enzyme that catalyzes the removal of sialic acid residues from glycoproteins, we initiated our studies using plant derived natural product honokiol to examine the effect of honokiol on Neu1. In this study, we demonstrated that honokiol suppressed Neu1 in two breast cancer cell lines using Western Blot Analysis. To determine whether there is a link between Neu1 and MRP1 in improving the efficacy of doxorubicin-facilitated growth suppression, we treated the breast cancer cells with Neu1 inhibitor, Oseltamivir Phosphate (OP) and demonstrated that at 600 ug/ml and 800 ug/ml, OP suppressed breast cancer cell growth. OP in combination with doxorubicin reduced growth of breast cancer cells and enhanced the efficacy of doxorubicin-mediated growth inhibition. Future studies are underway to examine the effect of OP and honokiol on the glycosylation of MRP1. We propose that these studies will lead to the understanding on how glycosylation of MRP1 contributes to the transport of chemotherapeutic agents and eventually to the spread of the disease. Citation Format: Padmamalini Thulasiraman, Kelbie Kerr. Understanding the crosstalk between glycosylation and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4890.