title: Decreased apoptosis repressor with caspase recruitment domain confers resistance to sunitinib in renal cell carcinoma through alternate angiogenesis pathways.
abstract: Apoptosis repressor with caspase recruitment domain (ARC), an endogenous inhibitor of apoptosis, is upregulated in a number of human cancers, thereby conferring drug resistance and giving a rationale for the inhibition of ARC to overcome drug resistance. Our hypothesis was that ARC would be similarly upregulated and targetable for therapy in renal cell carcinoma (RCC). Expression of ARC was assessed in 85 human RCC samples and paired non-neoplastic kidney by qPCR and immunohistochemistry, as well as in four RCC cell lines by qPCR, Western immunoblot and confocal microscopy. Contrary to expectations, ARC was significantly decreased in the majority of clear cell RCC and in three (ACHN, Caki-1 and 786-0) of the four RCC cell lines compared with the HK-2 non-cancerous human proximal tubular epithelial cell line. Inhibition of ARC with shRNA in the RCC cell line (SN12K1) that had shown increased ARC expression conferred resistance to Sunitinib, and upregulated interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). We therefore propose that decreased ARC, particularly in clear cell RCC, confers resistance to targeted therapy through restoration of tyrosine kinase-independent alternate angiogenesis pathways. Although the results are contrary to expectations from other cancer studies, they were confirmed here with multiple analytical methods. We believe the highly heterogeneous nature of cancers like RCC predicate that expression patterns of molecules must be interpreted in relation to respective matched non-neoplastic regions. In the current study, this procedure indicated that ARC is decreased in RCC.
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia.
authors.forename: Glenda C
authors.initials: GC
authors.lastname: Gobe
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia; Department of Urology, Princess Alexandra Hospital, Wollongabba Queensland, Australia.
authors.forename: Keng Lim
authors.initials: KL
authors.lastname: Ng
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Small
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia; Department of Renal Medicine, The University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, 4102, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Vesey
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia; Department of Renal Medicine, The University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, 4102, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia; Aquesta Pathology, Brisbane, Australia.
authors.forename: Hemamali
authors.initials: H
authors.lastname: Samaratunga
authors.affiliation: Anatomical Pathology, Princess Alexandra Hospital, Wollongabba, Queensland, Australia.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Oliver
authors.affiliation: Department of Urology, Princess Alexandra Hospital, Wollongabba Queensland, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Wood
authors.affiliation: Mater Research Institute, University of Queensland, Australia.
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Barclay
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia; Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.
authors.forename: Retnagowri
authors.initials: R
authors.lastname: Rajandram
authors.affiliation: Laboratory of Translational Cancer Research, Ochsner Health System, New Orleans, LA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia. Electronic address: c.morais@uq.edu.au.
authors.forename: Christudas
authors.initials: C
authors.lastname: Morais
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D007211:Indoles; D009419:Nerve Tissue Proteins; D011758:Pyrroles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C092069:activity regulated cytoskeletal-associated protein; D000077210:Sunitinib
keywords: ARC; Angiogenesis; Drug resistance; Renal cell carcinoma; Sunitinib