Abstract
Sunitinib resistance is a major clinical problem hampering the treatment of renal cell carcinoma (RCC). Studies on the comprehensive characterisation of morphological, functional and molecular changes in sunitinib-resistant RCC cells are lacking. The aim of the current study was to develop sunitinib resistance in four human RCC cell lines (786-0, Caki-1, Caki-2 and SN12K1), and to characterise the changed cell biology with sunitinib resistance. RCC cells were made resistant by continuous, chronic exposure to 10 μM of sunitinib over a period of 12 months. Cell proliferation, morphology, transmigration, and gene expression for interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), Bcl-2 and Bax were studied. There was no significant difference in growth rate or transmigration between the parental and resistant cells. Sunitinib-resistant cells were significantly hypertrophic compared with parental cells as evidenced by increases in the surface areas of the whole cells and the nuclei. IL-6 was significantly increased in all resistant cells. IL-8 was increased in sunitinib-resistant Caki-2 and SN12K1 cells and decreased in 786-0 without any significant changes in Caki-1. VEGF was increased in resistant Caki-2 and SN12K1 cells but not in 786-0 and Caki-1. The Bcl2/Bax ratio was increased in Caki-1, Caki-2 and SN12K1 cells but decreased in 786-0 cells. The increased IL-6 may contribute to sunitinib resistance either via VEGF-mediated angiogenesis or through shifting of the Bcl2/Bax balance in favour of anti-apoptosis.
Highlights
Vascular endothelial growth factor receptor (VEGFR)- targeted tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for metastatic renal cell carcinoma (RCC)
Activation of alternate angiogenesis pathway is the result of a myriad of molecules including ATX [21], chemokines [22], Cox-2 [23], EMMPRIN [24], HDM2, HDMX [25], IL-8 [26], IL-6 [27, 28], LPA [21], MDSC [29], NGAL [30], PRKX [31], PTEN [32], microRNAs [33] and many more emerging molecules and signalling pathways
We established four human RCC cell lines that are resistant to sunitinib, and characterised their morphological, functional and possible molecular mechanisms of sunitinib resistance
Summary
Vascular endothelial growth factor receptor (VEGFR)- targeted tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for metastatic renal cell carcinoma (RCC). Sunitinib is one of the first-line TKIs [1,2,3,4,5] that targets multiple receptor tyrosine kinases such as VEGFR-1, VEGFR-2 and VEGFR-3; platelet-derived growth factor receptor alpha (PDGFR)-α and (PDGFR)-β; stem cell growth. The mechanisms behind sunitinib resistance can be grouped under two major categories: reduced bioavailability and activation of alternate angiogenesis pathways. To the best of our knowledge, studies on comprehensive characterisation of the morphological, functional and molecular changes in sunitinib-resistant RCC cells are lacking. We established four human RCC cell lines that are resistant to sunitinib, and characterised their morphological, functional and possible molecular mechanisms of sunitinib resistance
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