Knockdown of platinum‐induced growth differentiation factor 15 abrogates p27‐mediated tumor growth delay in the chemoresistant ovarian cancer model A2780cis

Abstract

Molecular mechanisms underlying the development of resistance to platinum-based treatment in patients with ovarian cancer remain poorly understood. This is mainly due to the lack of appropriate in vivo models allowing the identification of resistance-related factors. In this study, we used human whole-genome microarrays and linear model analysis to identify potential resistance-related genes by comparing the expression profiles of the parental human ovarian cancer model A2780 and its platinum-resistant variant A2780cis before and after carboplatin treatment in vivo. Growth differentiation factor 15 (GDF15) was identified as one of five potential resistance-related genes in the A2780cis tumor model. Although A2780-bearing mice showed a strong carboplatin-induced increase of GDF15 plasma levels, the basal higher GDF15 plasma levels of A2780cis-bearing mice showed no further increase after short-term or long-term carboplatin treatment. This correlated with a decreased DNA damage response, enhanced AKT survival signaling and abrogated cell cycle arrest in the carboplatin-treated A2780cis tumors. Furthermore, knockdown of GDF15 in A2780cis cells did not alter cell proliferation but enhanced cell migration and colony size in vitro. Interestingly, in vivo knockdown of GDF15 in the A2780cis model led to a basal-enhanced tumor growth, but increased sensitivity to carboplatin treatment as compared to the control-transduced A2780cis tumors. This was associated with larger necrotic areas, a lobular tumor structure and increased p53 and p16 expression of the carboplatin-treated shGDF15-A2780cis tumors. Furthermore, shRNA-mediated GDF15 knockdown abrogated p27 expression as compared to control-transduced A2780cis tumors. In conclusion, these data show that GDF15 may contribute to carboplatin resistance by suppressing tumor growth through p27. These data show that GDF15 might serve as a novel treatment target in women with platinum-resistant ovarian cancer.

Cisplatin-induced ERK1/2 activity promotes G1 to S phase progression which leads to chemoresistance of ovarian cancer cells

“…Ovarian cancer cell lines used in our studies had constitutively phosphorylated ERK1/2, but it should be noted that cells resistant to cisplatin had these proteins phosphorylated to a significantly higher degree. Intensified basal activity of various kinases is wildly observed in ovarian cancer cells resistant to chemotherapeutic agents [ 17 , 18 ]. The response of the tested cells to the cisplatin treatment was obviously dependent on three parameters, the drug dose, time of exposure and, most importantly, nature of the cancer cells.…”

HE4 promotes collateral resistance to cisplatin and paclitaxel in ovarian cancer cells

“…EGR1 is a transcriptional regulator of growth differentiation factor 15 ( GDF15 ) [ 38 ], which was also upregulated in SKOV3-NV by cisplatin but not in SKOV3-C1 cells. While GDF15 has been linked to platinum resistance in pancreatic cancer [ 39 ] and ovarian cancer [ 40 ], it has also been shown to be a common platinum-responsive gene [ 41 , 42 ], and was identified as a potential serum marker for cisplatin-response of ovarian cancer cells [ 43 ]. Thus, the fact that it is not upregulated by cisplatin in SKOV3-C1 cells is also indicative of their dampened cisplatin resistance.…”

Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer

“…The mechanisms underlying the platinum resistance observed in A2780cis have not been fully identified. Upregulation of cell proliferation markers [ 39 ], members of the Akt signalling pathway [ 40 , 41 ], DNA-repair mechanisms [ 26 ] and ATP-dependent processes [ 42 ], and reduction in the copper transporter CTR1, thus preventing platinum accumulation [ 43 ] are among the suggested influences. We compared A2780 and A2780cis at the whole genome level in order to further identify mechanisms by which A2780cis has become resistant to cisplatin.…”