Abstract
Despite the use of front-line anticancer drugs such as paclitaxel for ovarian cancer treatment, mortality rates have remained almost unchanged for the past three decades and the majority of patients will develop recurrent chemoresistant disease which remains largely untreatable. Overcoming chemoresistance or preventing its onset in the first instance remains one of the major challenges for ovarian cancer research. In this study, we demonstrate a key link between senescence and inflammation and how this complex network involving the biomarkers MAD2, TLR4 and MyD88 drives paclitaxel resistance in ovarian cancer. This was investigated using siRNA knockdown of MAD2, TLR4 and MyD88 in two ovarian cancer cell lines, A2780 and SKOV-3 cells and overexpression of MyD88 in A2780 cells. Interestingly, siRNA knockdown of MAD2 led to a significant increase in TLR4 gene expression, this was coupled with the development of a highly paclitaxel-resistant cell phenotype. Additionally, siRNA knockdown of MAD2 or TLR4 in the serous ovarian cell model OVCAR-3 resulted in a significant increase in TLR4 or MAD2 expression respectively. Microarray analysis of SKOV-3 cells following knockdown of TLR4 or MAD2 highlighted a number of significantly altered biological processes including EMT, complement, coagulation, proliferation and survival, ECM remodelling, olfactory receptor signalling, ErbB signalling, DNA packaging, Insulin-like growth factor signalling, ion transport and alteration of components of the cytoskeleton. Cross comparison of the microarray data sets identified 7 overlapping genes including MMP13, ACTBL2, AMTN, PLXDC2, LYZL1, CCBE1 and CKS2. These results demonstrate an important link between these biomarkers, which to our knowledge has never before been shown in ovarian cancer. In the future, we hope that triaging patients into alterative treatment groups based on the expression of these three biomarkers or therapeutic targeting of the mechanisms they are involved in will lead to improvements in patient outcome and prevent the development of chemoresistance.
Highlights
Ovarian cancer is a major cause of cancer death in women worldwide with less than 40% of women surviving beyond 5 years post-diagnosis [1]
In order to discern a possible relationship between mitotic arrest deficient 2 (MAD2) and toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88) signalling, transfection experiments were performed initially in both A2780 (MyD88 null) and SKOV-3 (MyD88 positive) ovarian cancer cells (Fig 1)
Indicating that TLR4-MyD88 signalling and MAD2 were independent or at the very least that MAD2 expression was not influenced by changes in TLR4 or MyD88 expression in these cell models
Summary
Ovarian cancer is a major cause of cancer death in women worldwide with less than 40% of women surviving beyond 5 years post-diagnosis [1] This is due mainly to the development of recurrent chemoresistant disease which cannot as of yet be effectively treated in patients once it develops [2]. The TLR4 downstream adaptor molecule MyD88 was found to be prognostic in this largescale cohort in agreement with a number of other studies including our own [6, 8, 15, 23,24,25] Given these findings and the fact that paclitaxel is a known ligand for TLR4 [20], further interrogation of how this pathway contributes to paclitaxel chemoresistance is warranted
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