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Page 284 Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18
2 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University,
Abha, Saudi Arabia
3 UQ-Ochsner Clinical School, Ochsner Clinic Foundation, New Orleans, LA, USA
4 Departments of Urology and Nephrology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
5 UQ NHMRC CKD.QLD CRE, Royal Brisbane and Women’s Hospital, Brisbane, Australia

Renal cell carcinoma (RCC) accounts for 2%-3% of all adult malignancies and its incidence has risen over
past decades. If untreated, RCC is associated with high rates of metastasis and high mortality, partially
due to high levels of drug resistance. The novel gold-standard tyrosine kinase inhibitor, Sunitinib, targets
angiogenesis and other multiple pathways in RCC treatment. Sunitinib-resistance is a major clinical prob-
lem for treatment of RCC. The comprehensive characterisation of morphological, functional and molecular
changes in Sunitinib-resistant RCC cells is lacking. We aimed to develop Sunitinib-resistant human RCC
cell lines (SN12K1, Caki-1, Caki-2 and 786-0) and characterise the cellular biological changes. RCC cells
were made resistant by continuous, chronic exposure to 10 µmol/L Sunitinib. Resistant RCC cell lines were
stable in 10 µmol/L Sunitinib for nearly 2 years, while in parental cell lines, 10 µmol/L Sunitinib induced
95%-98% cell death at 72-h. Cell proliferation, morphology, transmigration, a cellular adhesion assay, and
gene expression (Q-RT-PCR) for vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, Bcl-
2 and Bax were studied. There was no significant difference in growth rate and 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. VEGF was in-
creased in Caki-2 and SN12K1 resistant cells by 5 and 2-fold, respectively. IL-6 was increased significantly
in 786-0, Caki-1, Caki-2 and SN12K1 resistant cells by 3.5, 2, 2 and 12-fold, respectively. IL-8 increased in
Sunitinib-resistant Caki-2 and SN12K1 cells by 2 and 2.5-fold, respectively. The Bcl2/Bax ratio increased
in Caki-1, Caki-2, and SN12K1 cells by 1.5, 2, and 2-fold, respectively, indicating increased apoptosis resis-
tance. Elevated IL-6 may contribute to Sunitinib resistance either via VEGF-mediated angiogenesis or anti-
apoptotic Bcl2. Thus inhibition of IL-6 could be a promising way to overcome drug resistance.

35. PEA-15 unphosphorylated at both serine 104 and serine 116 sensitizes ovarian carcinoma
cells to cisplatin

4
1
2
4
Shahana Dilruba , Anke C. Schiedel , Naoto T. Ueno , Florian Rothweiler , Jindrich Cinatl Jr ,
3
5
Martin Michaelis , Ganna V. Kalayda 1
1 Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Germany
2 Institute of Pharmacy, Pharmaceutical Chemistry I, University of Bonn, Germany
3 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston,
TX, USA
4 Institute of Medical Virology, Goethe University Hospital Frankfurt, Frankfurt/Main, Germany
5 Industrial Biotechnology Centre and School of Biosciences, School of Biosciences, University of Kent, Canter-
bury, UK

Cisplatin belongs to the standard chemotherapy regimens of various solid tumors. extracellular signal-
regulated kinase 1 and 2 (ERK1/2) is activated following cisplatin treatment. Upon activation, ERK1/2
shuttles between different cellular compartments, where it acts on various targets. Intracellular traffick-
ing of ERK1/2 is regulated, among others, by a small scaffold protein PEA-15 (phosphoprotein enriched in
astrocytes-15kDa). Depending on its phosphorylation at serine 104 and serine 116, PEA-15 can sequester
ERK1/2 in the cytoplasm or facilitate its nuclear translocation. In addition, PEA-15 mediates other cellular
processes such as autophagy and apoptosis. These functions of PEA-15 have also controlled its phosphory-