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RENCÜZOĞULLARI, ÖZGE

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Dr. Öğr. Üyesi

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RENCÜZOĞULLARI

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ÖZGE

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2017 - 201992020 - 202417
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    The Role of the PI3K/AKT/mTOR Signaling Axis in the Decision of the Celastrol-Induced Cell Death Mechanism Related to the Lipid Regulatory Pathway in Prostate Cancer Cells
    (Elsevier, 2020) RENCÜZOĞULLARI, ÖZGE; Çoban, Mervenur; Sevgin, Bortecine; Çoker-Gürkan, Ajda; YERLİKAYA, PINAR OBAKAN; Palavan-Ünsal, Narcin; ARISAN, ELİF DAMLA
    Prostate cancer is one of the leading cancer types among the male population worldwide, with high incidence and mortality rates. Celastrol is a promising bioactive component extracted from Tripterygium wilfordi. Celastrol is a multimodal agent with therapeutic advantages, with activities that affect cell proliferation, inflammation (through affecting proteotoxic stress) and cell death mechanisms such as autophagy, apoptosis and paraptosis. Celastrol alters the PI3K/AKT signaling axis to suppress the cell viability of cancer cells. Although a number of celastrol targets have been identified in cancer cells, the genomic differences in malignant cells prevent the efficacy of celastrol. Therefore, new studies are required to highlight its potential therapeutic effects in cancer cells. In this study, we investigated the therapeutic potential of celastrol in LNCaP, DU145 and PC3 prostate cancer cells. According to our results, celastrol decreased cell viability in a dose-dependent manner in the cells. LNCaP prostate cancer cells were more sensitive to celastrol treatment compared to DU145 and PC3 cells. We found that celastrol modulated PI3K/AKT/mTOR signaling to alter lipid regulatory pathways by affecting LAMP -1 and lipin-1 in PC3 cells. Although celastrol downregulated FASN in all cell lines, active mTOR signaling led to altered responses in prostate cancer cells by affecting the cellular fate decision pathways.
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    Celastrol Modulates Lipid Synthesis via PI3K/Akt/mTOR Signaling Axis to finalize Cell Death Response in Prostate Cancer Cells
    (2017) Çoker Gürkan, Ajda; Ünsal, Zeynep Narçin; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; RENCÜZOĞULLARI, ÖZGE; 113920; 222563; 125860; 156421; 6125
    FASN is key enzyme during lipid biogenesis is associated with prostate cancer. In this study, we aim to investigate the potential role of celastrol, root extracts of Tripterygium wilfordii on modulation of lipid biosynthesis-associated PI3K/Akt signaling. To determine the effect of celastrol on cell viability, prostate cancer cells were exposed with celastrol in dose dependent manner. AR (+) LNCaP and AR (−) DU145 and PC3 cell viability were inhibited by celastrol with IC50 in the range of 0.05–1 µM. To address the role of celastrol on cell death mechanism, celastrol-treated prostate cancer cells were evaluated with immunoblotting and flow cytometric analysis. Celastrol significantly upregulated PARP and caspase 9 cleavage also increased sub-G1 population. Celastrol also inhibited cell migration and invasion. These effects were associated with decreased PI3K/Akt signaling axis and downregulation of epithelial mesenchymal transition in prostate cancer cells. Likewise, lipid biosynthesis was downregulated with celastrol, however inhibition of PI3K/Akt signaling axis via LY294002 further decrease the cell migration and proliferation rate in prostate cancer cells. Our data suggest that, celastrol suppressed cell proliferation via inhibition of lipid biosynthesis through downregulation of PI3K/Akt signal axis. Targeting lipid metabolism-related enzymes in prostate cancer may offer new avenues for therapeutic approaches.
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    Palbociclib Negatively Regulates Fatty Acid Synthesis Due to Upregulation of AMPK Alpha and miR-33a Levels to Increase Apoptosis in Panc-1 and MiaPaCa-2 Cells
    (Wiley, 2022) RENCÜZOĞULLARI, ÖZGE; YERLİKAYA, PINAR OBAKAN; GÜRKAN, AJDA ÇOKER; Telci, Dilek; ARISAN, ELİF DAMLA
    Fatty acids (FAs) synthesis mechanism has various regulators such as fatty acid synthase (FASN), AMP-regulated protein kinase (AMPK), or mammalian target of rapamycin (mTOR), which are aberrantly dysregulated in various pancreatic cancer cells. In this study, we aim to understand the regulatory role of palbociclib, a CDK4/6 inhibitor, on the cellular energy metabolism through regulation of AMPK/mTOR signaling by modulation of intracellular miR-33a levels in Panc-1 and MiaPaCa-2 cells. Palbociclib downregulated FAs metabolism more effectively in MiaPaCa-2 cells than Panc-1 cells. Moreover, palbociclib treatment increased the levels of miR-33a in each cell line albeit a higher increase was evident in MiaPaCa-2 cells. Stress-mediated activation of mTOR signaling axis was found associated with palbociclib-mediated AMPK alpha activation and miR33a upregulation. These findings provided that a deeper understanding about possible interactions of cell cycle activity and reduction of FAs synthesis may facilitate the enhancement of cell death mechanisms in pancreatic cancer cells.
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    Diclofenac induced apoptosis via altering PI3K/Akt/MAPK signaling axis in HCT 116 more efficiently compared to SW480 colon cancer cells
    (Springer Link, 2018-12) Ergül, Zehragül; Bozdağ, Gülnihal; Ünsal, Zeynep Narçin; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; RENCÜZOĞULLARI, ÖZGE; COŞKUN, DENİZ; 113920; 222563; 125860; 156421; 6125
    Diclofenac is a preferential cyclooxygenase 2 inhibitor (COX-2) and member of non-steroidal anti-inflammatory drugs (NSAIDs). Inflammation is one of the main reason of poor prognosis of colon cancer cases; thereby NSAIDs are potential therapeutic agents in colon cancer therapy. In this study, our aim to understand the potential molecular targets of diclofenac, which may propose new therapeutic targets in HCT 116 (wt p53) and SW480 (mutant p53R273H) colon cancer cells. For this purpose, we identified different response against diclofenac treatment through expression profiles of PI3K/Akt/MAPK signaling axis. Our hypothesis was diclofenac-mediated apoptosis is associated with inhibition of PI3K/Akt/MAPK signaling axis. We found that sub-cytotoxic concentration of diclofenac (400 µM) promoted further apoptosis in HCT 116 cells compared to SW480 colon cancer cells. Diclofenac triggered dephosphorylation of PTEN, PDK, Akt, which led to inhibition of PI3K/Akt survival axis in HCT 116 colon cancer cells. However, diclofenac showed lesser effect in SW480 colon cancer cells. In addition, diclofenac further activated p44/42, p38 and SAPK/JNK in HCT 116 cells compared to SW480 cells.
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    Circulating MicroRNA Expression Profiles to Identify a Potential Link Between Prostate Cancer and Obesity
    (Elsevier, 2022) Arışan, Serdar; KILBAŞ, PELİN ÖZFİLİZ; RENCÜZOĞULLARI, ÖZGE; Ünsal, Narcin Palavan; Çoker-Gürkan, Ajda; Uysal-Onganer, Pınar; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN
    Effective diagnostic methods are needed to apply appropriate treatment strategies in patients with aggressive prostate cancer. From this point of view, risk factors that cause prostate cancer or its aggressiveness should be considered. Obesity is a critical risk factor for triggering prostate cancer's metastatic properties. microRNAs are used as biomarkers in diagnosing cancer and obesity depending on their tissue-specific expression patterns. This study investigates the role of obesity in the metastatic profile of prostate cancer depending on the differential expression signatures of selected miRNAs in prostate cancer and obese patients. The roles of miR-100, miR-141 and miR-145 in prostate cancer and obesity are partially known. However, their potential to become circular biomarkers in the blood is not elucidated. There is no previous data on miR-4463 and miR-653 on prostate cancer and obesity association. In this study, the blood samples were taken and obtained serum from 69 patients of 6 subgroups that consisted of one healthy group and five unhealthy groups based on their different prostate cancer or obesity levels. Five selected miRNA expression analyses (miR-100, miR-141, miR-145, miR-4463, and miR-653) were performed through total RNA isolation, which was confirmed via synthetic cel-miR-39 miRNA. Quantitative Real-Time PCR analyzed the expression levels of selected miRNAs. Data analysis was performed via normalising target miRNA expression levels with cel-miR-39. In this study, we found that the relationship between prostate cancer and obesity was investigated at the molecular level. It was suggested that target miR-100 could be a promising biomarker for non-obese and aggressive prostate cancer patients. miR-145 is a more potential biomarker than miR-141 for non-aggressive and non-obese patients. miR-4463 can be used to predict more prostate cancer patients than obese patients. Lastly, miR-653 can be a biomarker for non-aggressive prostate cancer cells.
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    Investigation of PI3K-AKT and EMT-targeted miRNA profiles in palbociclib-treated Panc-1 and MiaPaCa-2 pancreatic cancer cells
    (2019-07) Çoker Gürkan, Ajda; YERLİKAYA, PINAR OBAKAN; RENCÜZOĞULLARI, ÖZGE; 222563; 156421; 125860
    The therapeutic strategies of pancreatic cancer (PC) are with the various combination treatment of anti-cancer drugs still in progress. However, the survival rate o f PC is still under 6%. because o f the limited therapeutics and no controllable prognosis. miRNAs have an important role in tire regulation of metabolic cascades which are critical in the differentiation of PC progression. In the current study, we aimed to investigate the role o f palbociclib (CDK4/6 inhibitor) on aberrantly activated pathways, PI3K/AKT, and EMT signaling axis through differently expressed miRNA profiles in Pane-1 and MiaPaCa-2 cells. The effect of palbociclib on cell viability was detennined by MTT cell viability test in time and dose-dependent maimer in PC cells. The expression profiles were analyzed by RT-PCR. We found that palbociclib effectively reduced cell viability and proliferation for following exposure of Panc-1 and MiaPaCa-2 cells for 24h. Additively, Panc-1 and MiaPaCa-2 cells were sensitive to palbociclib with the significant blockade in the G1 phase o f the cell cycle. Palbociclib decreased the expression o f PI3K and p-AKT in PC cells. Moreover, palbociclib downregulated the levels of B-catenin in Panc-1 cells, but not in MiaPaCa-2 cells. Palbociclib treatment led to increased levels of tumor suppressor miR- 506, miR-100, and miR-141 in MiaPaCa-2 cells, while the only detectable increase in tumor suppressor miRNA was detected formiR-100 levels in Panc-1 cells. Additionally, the oncomir miR-208 increased after palbociclib treatment in MiaPaCa-2 cells. In conclusion, palbociclib induced cell cycle arrest and reduced cell viability. However, palbociclib had a various effect on the regulation of PI3K/AKT and EMT signaling in each PC cell line. Investigating the effect of palbociclib on the tumor suppressor and oncomir miRNA profiles is a new therapeutic strategy to reduce cell viability and metastatic process of pancreatic cancer.
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    Palbociclib, a selective CDK4/6 inhibitor, restricts cell survival and epithelial-mesenchymal transition in Panc-1 and MiaPaCa-2 pancreatic cancer cells
    (2020-01-01) Telci, D.; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; RENCÜZOĞULLARI, ÖZGE
    The mortality rate of pancreatic cancer has close parallels to its incidence rate because of limited therapeutics and lack of effective prognosis. Despite various novel chemotherapeutics combinations, the 5-year survival rate is still under 5%. In the current study, we aimed to modulate the aberrantly activated PI3K/AKT pathway and epithelial-mesenchymal transition (EMT) signaling with the treatment of CDK4/6 inhibitor PD-0332991 (palbociclib) in Panc-1 and MiaPaCa-2 pancreatic cancer cells. It was found that PD-0332991 effectively reduced cell viability and proliferation dose-dependently within 24 hours. In addition, PD-0332991 induced cell cycle arrest at the G1 phase by downregulation of aberrant expression of CDK4/6 through the dephosphorylation of Rb in each cell lines. Although PD-0332991 treatment increased epithelial markers and decreased mesenchymal markers, the nuclear translocation of β-catenin was not prevented by PD-0332991 treatment, especially in MiaPaCa-2 cells. Effects of PD-0332991 on the regulation of PI3K/AKT signaling and its downstream targets such as GSK-3 were cell type-dependent. Although the activity of AKT was inhibited in both cell lines, the phosphorylation of GSK-3β at Ser9 increased only in Panc-1. In conclusion, PD-0332991 induced cell cycle arrest and reduced the cell viability of Panc-1 and MiaPaCa-2 cells. However, PD-0332991 differentially affects the regulation of the PI3K/AKT pathway and EMT process in cells due to its distinct influence on Rb and GSK-3/β-catenin signaling. Understanding the effect of PD-0332991 on the aberrantly activated signaling axis may put forward a new therapeutic strategy to reduce the cell viability and metastatic process of pancreatic cancer. © 2019 Wiley Periodicals, Inc.
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    Gemcitabine in Combination With Epibrassinolide Enhanced the Apoptotic Response in an ER Stress-Dependent Manner and Reduced the Epithelial-Mesenchymal Transition in Pancreatic Cancer Cells
    (TUBITAK Scientific & Technical Research Council Turkey, 2022) Mehdizadehtapeh, Leila; RENCÜZOĞULLARI, ÖZGE; KURYAYEVA, FADINA; ÇEVİKLİ, SENA SEDEF; ÖZAGAR, SEVVAL; ODABAŞ, PINAR SİBEL; TUNÇKOL, SUDE; YETİM, HAKAN; Gürkan, Ajda Çoker; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN
    Gemcitabine is a broad-spectrum antimetabolite and a deoxycytidine analog recognized as a standard therapy alone or in combination with other antineoplastic agents in the therapy of pancreas cancer. Drug resistance following gemcitabine treatment is a common phenomenon; therefore, combinational therapy models are usually preferred. Pancreatic ductal adenocarcinoma, or pancreas cancer, is the fourth leading cause of cancer-related deaths worldwide. With the increasing incidence of pancreatic cancer every year, the mortality rate is also rising significantly because of late diagnosis, and limited chemotherapy options. Adjuvant chemotherapy after surgical resection is the typical option for the treatment of early pancreatic cancer. Mostly, 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel is used for the prognosis of advanced pancreatic cancer; however, chemoresistance usually occurs limiting the effectiveness of the chemotherapy. Therefore, most of the studies are focused on gemcitabine combination with other drugs to overcome the situation.As an apoptotic agent and a member of brassinosteroids, epibrassinolide (EBR) induces endoplasmic reticulum (ER) stress-dependent cell death in different cancer cells, as shown by our group. In this study, we aimed to enhance the gemcitabine apoptotic effect by EBR combined treatment in pancreatic cancer cells. EBR treatment reduced cell viability and inhibited cell proliferation in PANC-1, MIA PaCa-2, and AsPC-1 cells. Each pancreatic cancer cell gave different responses to the EBR treatment because of different aggressiveness. However, EBR induced apoptosis through increasing ROS generation, which was associated with ER stress in PANC-1 and MIA PaCa-2 cells. Gemcitabine alone reduced the cell viability of each pancreatic cancer cell line; however, combination with EBR led to further induction of apoptotic cell death in each pancreatic cancer cell line. In addition, combined treatment of gemcitabine and EBR further decreased N-cadherin and vimentin expressions, suggesting that epithelial-mesenchymal transition of pancreatic cells is reduced. In conclusion, EBR had therapeutic potential to avoid the gemcitabine-induced side effects during the treatment of pancreatic cancer.
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    Investigation the Role of Palbociclib on Fatty Acid Synthase Metabolism through Regulation of miR-33a in Pancreatic Cancer Cells
    (2019-05-16) Telci, Dilek; ARISAN, ELİF DAMLA; RENCÜZOĞULLARI, ÖZGE; 222563; 34170; 113920
    Aberrant activation of fatty acid (FA) synthesis is associated with cancer development including pancreatic cancer (PC). SREBP is an important regulator of FA synthesis and modulated by growth factor signaling which is also targeted by miR-33a. We aim to determine the role of palbociclib, CDK4/6 inhibitor, on the regulation of FA synthase metabolism through targeting regulators of SREBP such as miR-33a in PC cells. The expression profiles of FA metabolism signaling axis were examined by immunoblotting. The levels of miRNA profiles were analyzed by RT-PCR. Oil red O staining determined the oil droplets in PC cells. Palbociclib exerted a controversial effect on the expression of FA synthesis signaling axis such as FASN, ACL in Panc-1 and MiaPaCa-2 cells. Palbociclib treatment increased the expression of FASN, p-ACL, and ACSL-1 in Panc-1 cells. However, the expression levels of mature SREBP2 were decreased by palbociclib treatment and overexpression of miR-33a resulted in a further decrease of precursor and mature SREBP protein levels in Panc-1 cells. Moreover, inhibition of miR-33a significantly upregulated the SREBP levels in palbociclib-treated Panc-1 cells. The content of lipid drops in Panc-1 cells was more reduced after co-treatment of miR33a with palbociclib. In conclusion, key regulatory factors of lipid metabolism such as FASN, SREBP are important targets to control PC cell proliferation. Overexpression of miR-33a decreased the level of SREBP2 which indicated the downregulation of FA metabolism. It was suggested that the effect of palbociclib on the downregulation of FA synthesis and cell viability was further increased by SREBP targeted-miR-33a.