CDK6 protects epithelial ovarian cancer from platinum‐induced death via FOXO3 regulation

Abstract

Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum‐based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum‐treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.

TIMP-1 Is Overexpressed and Secreted by Platinum Resistant Epithelial Ovarian Cancer Cells

“…Dose-response curves were performed essentially as described previously [9,16,17]. Briefly, EOC cells were seeded in 96-well culture plates and treated with increasing doses of cispaltin (TEVA Italia) for 72 h. For treatment with recombinant human TIMP-1 (R&D Systems), TOV-112D and OVSAHO parental cells were treated with increasing doses of CDDP in combination or not with the recombinant protein (100 ng/mL) for 16 h. Cell viability was analyzed 24 h after CDDP removal by MTS assay using the CellTiter 96 AQueous cell proliferation assay kit (Promega)…”

Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells

“…Dose-response curves were performed essentially as previously described [13,14]. Briefly, EOC cells were seeded in 96-well culture plates and treated with increasing doses of cisplatin (CDDP) (TEVA Italia) for 72 h. For dose-response curves of p53-silenced MDAH, cells were seeded in 96-well culture plates and after 24 h transduced with sh-ctrl or sh-p53 lentiviral particles (Mission Sigma TRCN0000003756).…”

“…p53 protein stability was evaluated in MDAH-2774 parental and PT-res clones (#12 and #42) treated with CHX (10 mg/mL) for the indicated time points using procedures as previously described in references [13,14].…”

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

“…The knockdown of MCPH20 in DU145 and PC3 PCa cells induced cell apoptosis [36]. Consistently, high expression of MCPH12 affects cell apoptosis by altering the cell cycle process, leading to the occurrence of various cancers [67,116]. In contrast, MCPH1 is an early DNA damage response protein [117].…”

“…Regulating radial glial cells G1 and S phases [66] DNA damage response, apoptosis (epithelial ovarian cancer) [67] Positively regulates the proliferation of hippocampal progenitors [68] Cell cycle (glioblastoma) [69] Proliferation of neural stem cells [70] Cell cycle, cell proliferation and angiogenesis (hematopoietic malignancies) [71] Cell cycle and apoptosis (T-cell acute lymphoblastic leukemia) [72] MCPH13 (CENPE) N/A Cell G2/M phase and proliferation (lung cancer) [25] MCPH14 (SAS6) N/A Centrosome amplification, mitotic abnormality (CRCs) [73] MCPH15 (MFSD2A) Blood-brain barrier disruption [74] Cell cycle (G1 phase) and matrix attachment (lung cancer) [41] MCPH16 (ANKLE2) Reduced cell proliferation [75] N/A…”