Ankyrin Repeat Domain 1, ANKRD1, a Novel Determinant of Cisplatin Sensitivity Expressed in Ovarian Cancer

Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
Clinical Cancer Research (Impact Factor: 8.72). 11/2008; 14(21):6924-32. DOI: 10.1158/1078-0432.CCR-07-5189
Source: PubMed


The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics.
Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma.
The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P=0.013).
These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.

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    • "Furthermore, we identified ASB9 (ankyrin repeat and SOCS box containing 9) to be associated with oxaliplatin resistance. Several ankyrin-related genes have previously been associated with chemotherapy resistance or apoptosis (Santoni and Farfariello, 2011; Scurr et al., 2008). AKT3 was also among our identified genes and has previously been implicated in cisplatin resistance (Gagnon et al., 2004). "
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    • "Although in vivo evidence about the influence of CARP on the growth of cardiomyocytes is scant, there are several lines of evidence which suggest that Ankrd1/CARP promotes non-cardiomyocyte cell growth rather than inhibiting it. For example, CARP was reported to promote neurite outgrowth in F11 cells [28], as well as the growth of cancer cells [29] and neovascularization in tissue wounds [30]. "
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    • "To determine the molecular mechanisms by which M0505 cells transformed into the STOSE cells, whole genome microarray analysis was performed on M0505 and STOSE cells and linear fold changes were calculated for STOSE cells relative to M0505 cells. The top 10 up- and down-regulated genes in STOSE compared to M0505 cells are presented in Table 2. Interestingly, Ddr2, Ereg, Glipr1, Calcr, and Ankrd1, all up-regulated in STOSE cells, have been shown to be up-regulated in primary tumors and ovarian cancer cells (21–24). Igfbp4 has been shown to be down-regulated in primary tumors (25, 26). "
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