Mahmoud Aghaei

Targeting the PERK/NRF2 pathway: Enhancing cisplatin efficacy in resistant ovarian cancer cells via MRP1 and ROS modulation

Overcoming chemotherapy resistance remains a pivotal challenge in ovarian cancer treatment. This study investigates the potential of combining cisplatin with GSK2606414, a PERK inhibitor, to enhance therapeutic efficacy against cisplatin-resistant ovarian cancer cells. cisplatin resistance is driven by the PERK/NRF2 pathway, which activates MRP1 upregulation and antioxidant defenses, thus promoting cell survival. By inhibiting PERK phosphorylation, GSK2606414 disrupts this pathway, downregulating MRP1 and increasing oxidative stress to sensitize cancer cells to cisplatin. Our findings reveal that the GSK2606414-cisplatin combination significantly reduces cell viability and proliferation, particularly in resistant cell lines, allowing for dose reduction and potentially lower side effects. The combined therapy also amplifies, increasing Caspase-12 and CHOP protein levels during endoplasmic reticulum stress. By targeting the p-PERK/p-NRF2/MRP1 and p-PERK/p-NRF2/SOD pathways, GSK2606414 decreases MRP1 expression and elevates ROS levels, rendering resistant cells more susceptible to chemotherapy. Additionally, this combination boosts intracellular cisplatin accumulation in both cisplatin-sensitive and -resistant ovarian cancer cell lines, reinforcing its cytotoxic impact. These findings underscore the promise of GSK2606414 and cisplatin co-treatment as a potent strategy to counteract ovarian cancer resistance. This combination could potentially advance therapeutic outcomes and provide a new pharmacological approach to resistant cancers.

Molecular mechanisms of miR‐1236 in the assessment of tumor lymphangiogenesis in human ovarian cancer patients

AbstractBackgroundTumor lymphangiogenesis is a critical component in the progression of cancers and specific microRNAs have been reported to be implicated in this process. Recent studies revealed the involvement of miR‐1236 in lymphangiogenic signaling by targeting vascular endothelial growth factor receptor 3 (VEGFR3). However, the prognostic importance of miR‐1236 and its clinical relevance for lymphangiogenesis in ovarian cancer (OC) remains unclear.MethodsThe study included 52 ovarian tumors and 28 normal ovarian tissues. Quantitative real‐time PCR was utilized to analyze the VEGFR3, VEGF‐C, LYVE‐1 and PROX1 mRNA expression as well as miR‐1236. VEGFR3 protein expression was measured by immunohistochemistry staining. Immunohistochemistry for the podoplanin marker (D2‐40) was performed to measure lymphatic vessel density (LVD). In addition, diagnostic evaluation based on the receiver‐operating characteristic (ROC) curve was performed. The influence of miR‐1236 on overall survival was evaluated by Kaplan–Meier method.ResultsHere, we show that miR‐1236 expression was significantly decreased in ovarian tumors compared with control tissues (p < 0.001) and correlated with advanced clinical stage, lymph node metastasis, distant metastasis and patient survival (All P < 0.05). Moreover, in ovarian tumors, LVD as well as the gene expression of VEGFR3, VEGF‐C and LYVE‐1, but not PROX1, were found to be remarkably higher compared with control tissues. We also detected a more robust positive staining for VEGFR3 in OC tissues than in control tissues. Furthermore, our results demonstrated an inverse association of miR‐1236 expression with LVD, VEGFR3, LYVE‐1 and PROX1 expression in OC tissues. The ROC curve analysis indicated that miR‐1236 expression has the potential to be used as a diagnostic and prognostic biomarker in OC. Survival analysis further verified a lowered overall survival rate in patients with low miR‐1236 expression than in those with high expression.ConclusionsOur results provide evidence for the translational involvement of miR‐1236 in the lymphangiogenesis of OC by regulating lymphangiogenesis‐related factors and support the clinical importance of miR‐1236 as a new diagnostic and prognostic biomarker for OC.

VEGFR3 suppression through miR‐1236 inhibits proliferation and induces apoptosis in ovarian cancer via ERK1/2 and AKT signaling pathways

AbstractVascular endothelial growth factor receptor 3 (VEGFR3) is expressed in cancer cell lines and exerts a critical role in cancer progression. However, the signaling pathways of VEGFR3 in ovarian cancer cell proliferation remain unclear. This study aimed to demonstrate the signaling pathways of VEGFR3 through the upregulated expression of miR‐1236 in ovarian cancer cells. We found that the messenger RNA and protein of VEGFR3 were expressed in the ovarian cancer cell lines, but downregulated after microRNA‐1236 (miR‐1236) transfection. The inhibition of VEGFR3, using miR‐1236, significantly reduced cell proliferation, clonogenic survival, migration, and invasion ability in SKOV3 and OVCAR3 cells (p < 0.01). The flow cytometry results indicated that the rate of apoptotic cells in SKOV3 (38.65%) and OVCAR3 (41.95%) cells increased following VEGFR3 inhibition. Moreover, VEGFR3 stimulation (using a specific ligand, VEGF‐CS) significantly increased extracellular signal‐regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation (p < 0.01), whereas VEGFR3 suppression reduced p‐ERK1/2 (67.94% in SKOV3 and 93.52% in OVCAR3) and p‐AKT (59.56% in SKOV3 and 78.73% in OVCAR3) compared to the VEGF‐CS treated group. This finding demonstrated that miR‐1236 may act as an endogenous regulator of ERK1/2 and AKT signaling by blocking the upstream regulator of VEGFR3. Overall, we demonstrated the important role of the miR‐1236/VEGFR3 axis in ovarian cancer cell proliferation by regulating the ERK1/2 and AKT signaling that might be an effective strategy against ovarian cancer.