Abstract
Objective: Investigating the role of Y-box binding protein 1 (YB1) in drug resistant advanced kidney cancer.
Background: Renal cell carcinoma (RCC) is the 6th most common malignancy with approximately 1,800 deaths in 2015 and 2.3% annual increase in Canada. Despite the partial or total surgical removal of kidney in patients with localized RCC, metastatic patients are treated with tyrosine kinase inhibitors (TKIs) in a purely palliative approach. However, TKI-resistance (Sunitinib) is developed after a median time of 10-14 months. Therefore, identifying the factor(s) responsible for TKI-resistance development and disease advancement in RCC is imperative. It is now widely recognized that evolutionarily conserved Y-box binding protein 1 (YB1) is essential for cell growth and survival. Upregulation of YB1 in numerous cancer types was found to be positively correlated with tumor growth, metastasis and drug-resistance development. YB1 is also involved in intercellular communication through its secretion in the tumor microenvironment by cell-surface transporters, ABC-transporters.
Summary of the data: Endothelial cells (HUVEC) were co-cultured with Caki-1DC (Sunitinib-resistant, developed in our lab) and Caki-1WT (Sunitinib-sensitive) RCC cell-lines, and increased migration of HUVEC was observed with Caki-1DC compared to Caki-1WT. A drastic increase in YB1 and its downstream target ABCB1 in Caki-1DC compared to Caki-1WT cells was also detected. Consistent with previous reports, we observed granular structures in the Caki-1DC cells that support potential secretion of YB1 into the tumor microenvironment. Moreover, blocking ABCB1 reverted the Caki-1DC cells to being drug-sensitive.
Experimental procedures: Caki-1WT and Caki-1DC were co-cultured with HUVEC cells followed by scratch assay to test for HUVEC cell migration and associated secretory factors. Western blot and qPCR were used to determine the protein and mRNA levels respectively between the two cell-lines. Immuno-histochemical staining was carried out on the RCC tumors from Sunitinib-sensitive and resistant mouse models (developed in our animal facility). Granular structures were observed using immunofluorescence staining against YB1. Presto-blue was used for cell biomass assay following different drug treatments.
Summary: The molecular function of YB1 in RCC and its potential in targeted therapy is not well understood. Therefore, understanding the function of YB1 in metastatic RCC and in drug-resistance development is of vital importance. Our data suggests that inhibition of YB1 may slow disease progression and, possibly, revert the drug resistance mechanism. The results from this study have the potential to introduce YB1 inhibitors in conventional RCC chemotherapy, alone or in combination, to improve survival in advanced kidney cancer patients.
Citation Format: Ninadh M. D'Costa, Peter Raven, Zheng Tan, Werner Struss, Sebastian Frees, Claudia Chavez-Munoz, Alan I. So. Y-box binding protein 1 is crucial in acquiring drug resistance in advanced renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3080. doi:10.1158/1538-7445.AM2017-3080
- ©2017 American Association for Cancer Research.
Volume 77, Issue 13 Supplement
