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Now showing 1 - 7 of 7
  • Publication
    Proinflammatory Cytokine Profile is Critical in Autocrine GH-Triggered Curcumin Resistance Engulf by Atiprimod Cotreatment in MCF-7 and MDA-MB-231 Breast Cancer Cells
    (Springer, 2020) Çoker-Gürkan, Ajda; Özakaltun, Buse; Akdeniz, Berre-Serra; Ergen, Berfin; YERLİKAYA, PINAR OBAKAN; Akkoç, Tunç; Arısan, Elif-Damla
    Active growth hormone (GH) signaling triggers cellular growth and invasion-metastasis in colon, breast, and prostate cancer. Curcumin, an inhibitor of NF-kappa B pathway, is assumed to be a promising anti-carcinogenic agent. Atiprimod is also an anti-inflammatory, anti-carcinogenic agent that induces apoptotic cell death in hepatocellular carcinoma, multiple myeloma, and pituitary adenoma. We aimed to demonstrate the potential additional effect of atiprimod on curcumin-induced apoptotic cell death via cytokine expression profiles in MCF-7 and MDA-MB-231 cells with active GH signaling. The effect of curcumin and/or atiprimod on IL-2, IL-4, and IL-17A levels were measured by ELISA assay. MTT cell viability, trypan blue exclusion, and colony formation assays were performed to determine the effect of combined drug exposure on cell viability, growth, and colony formation, respectively. Alteration of the NF-kappa B signaling pathway protein expression profile was determined following curcumin and/or atiprimod exposure by RT-PCR and immunoblotting. Finally, the effect of curcumin with/without atiprimod treatment on Reactive Oxygen Species (ROS) generation and apoptotic cell death was examined by DCFH-DA and Annexin V/PI FACS flow analysis, respectively. Autocrine GH-mediated IL-6, IL-8, IL-10 expressions were downregulated by curcumin treatment. Atiprimod co-treatment increased the inhibitory effect of curcumin on cell viability, proliferation and also increased the curcumin-triggered ROS generation in each GH(+) breast cancer cells. Combined drug exposure increased apoptotic cell death through acting on IL-2, IL-4, and IL-17A secretion. Forced GH-triggered curcumin resistance might be overwhelmed by atiprimod and curcumin co-treatment via modulating NF-kappa B-mediated inflammatory cytokine expression in MCF-7 and MDA-MB-231 cells.
  • Publication
    Open Access
    Epibrassinolide Activates AKT to Trigger Autophagy With Polyamine Metabolism in SW480 and DLD-1 Colon Cancer Cell Lines
    (The Scientific and Technological Research Council of Turkey, 2020) Adacan, Kaan; YERLİKAYA, PINAR OBAKAN
    Epibrassinolide (EBR), a plant-derived polyhydroxylated derivative of 5 alpha-cholestane, structurally shows similarities to animal steroid hormones. According to the present study, EBR treatment triggered a significant stress response via activating ER stress, autophagy, and apoptosis in cancer cells. EBR could also increase Akt phosphorylation in vitro. While the activation of Akt resulted in cellular metabolic activation in normal cells to proceed with cell survival, a rapid stress response was induced in cancer cells to reduce survival. Therefore, Akt as a mediator of cellular survival and death decision pathways is a crucial target in cancer cells. In this study, we determined that EBR induces stress responses through activating Akt, which reduced the mTOR complex I (mTORC1) activation in SW480 and DLD-1 colon cancer cells. As a consequence, EBR triggered macroautophagy and led to lipidation of LC3 most efficiently in SW480 cells. The cotreatment of spermidine (Spd) with EBR increased lipidation of LC3 synergistically in both cell lines. We also found that EBR promoted polyamine catabolism in SW480 cells. The retention of polyamine biosynthesis was remarkable following EBR treatment. We suggested that EBR-mediated Akt activation might determine the downstream cellular stress responses to induce autophagy related to polyamines.
  • Publication
    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) Arısan, Elif Damla; RENCÜZOĞULLARI, ÖZGE; Çoban, Mervenur; Sevgin, Bortecine; Çoker-Gürkan, Ajda; YERLİKAYA, PINAR OBAKAN; Palavan-Ünsal, Narcin
    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.
  • Publication
    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
    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.
  • Publication
    Open Access
    Specific c-Jun N-Terminal Kinase Inhibitor, JNK-IN-8 Suppresses Mesenchymal Profile of PTX-Resistant MCF-7 Cells through Modulating PI3K/Akt, MAPK and Wnt Signaling Pathways
    (MDPI, 2020) KILBAŞ, PELİN ÖZFİLİZ; Sönmez, Özlem; Uysal-Onganer, Pınar; Çoker Gürkan, Ajda; YERLİKAYA, PINAR OBAKAN; Arışan, Elif Damla
    Paclitaxel (PTX) is a widely used chemotherapeutic agent in the treatment of breast cancer, and resistance to PTX is a common failure of breast cancer therapy. Therefore, understanding the effective molecular targets in PTX-resistance gains importance in identifying novel strategies in successful breast cancer therapy approaches. The aim of the study was to investigate the functional role of PTX resistance on MCF-7 cell survival and proliferation related to PI3K/Akt and MAPK pathways. The generated PTX-resistant (PTX-res) MCF-7 cells showed enhanced cell survival, proliferation, and colony formation potential with decreased cell death compared to wt MCF-7 cells. PTX-res MCF-7 cells exhibited increased motility profile with EMT, PI3K/Akt, and MAPK pathway induction. According to the significant SAPK/JNK activation in PTX-res MCF-7 cells, specific c-Jun N-terminal kinase inhibitor, JNK-IN-8 is shown to suppress the migration potential of cells. Treatment of JNK inhibitor suppressed the p38 and SAPK/JNK and Vimentin expression. However, the JNK inhibitor further downregulated Wnt signaling members in PTX-res MCF-7 cells. Therefore, the JNK inhibitor JNK-IN-8 might be used as a potential therapy model to reverse PTX-resistance related to Wnt signaling.
  • Publication
    Epibrassinolide-Induced Autophagy Occurs in an Atg5-Independent Manner Due to Endoplasmic Stress Induction in MEF Cells
    (Springer, 2020) Adacan, Kaan; YERLİKAYA, PINAR OBAKAN; Arısan, Elif Damla; Çoker-Gürkan, Ajda; Kaya, Resul İsmail; Palavan-Ünsal, Narcin
    Epibrassinolide (EBR), a polyhydroxysteroid belongs to plant growth regulator family, brassinosteroids and has been shown to have a similar chemical structure to mammalian steroid hormones. Our findings indicated that EBR could trigger apoptosis in cancer cells via induction of endoplasmic reticulum (ER) stress, caused by protein folding disturbance in the ER. Normal cells exhibited a remarkable resistance to EBR treatment and avoid from apoptotic cell death. The unfolded protein response clears un/misfolded proteins and restore ER functions. When stress is chronic, cells tend to die due to improper cellular functions. To understand the effect of EBR in non-malign cells, mouse embryonic fibroblast (MEF) cells were investigated in detail for ER stress biomarkers, autophagy, and polyamine metabolism in this study. Evolutionary conserved autophagy mechanism is a crucial cellular process to clean damaged organelles and protein aggregates through lysosome under the control of autophagy-related genes (ATGs). Cells tend to activate autophagy to promote cell survival under stress conditions. Polyamines are polycationic molecules playing a role in the homeostasis of important cellular events such as cell survival, growth, and, proliferation. The administration of PAs has been markedly extended the lifespan of various organisms via inducing autophagy and inhibiting oxidative stress. Our data indicated that ER stress is induced following EBR treatment in MEF cells as well as MEF Atg5(-/-) cells. In addition, autophagy is activated following EBR treatment by targeting PI3K/Akt/mTOR in wildtype (wt) cells. However, EBR-induced autophagy targets ULK1 in MEF cells lacking Atg5 expression. Besides, EBR treatment depleted the PA pool in MEF cells through the alterations of metabolic enzymes. The administration of Spd with EBR further increased autophagic vacuole formation. In conclusion, EBR is an anticancer drug candidate with selective cytotoxicity for cancer cells, in addition the induction of autophagy and PA metabolism are critical for responses of normal cells against EBR.
  • Publication
    Open Access
    Endoplasmic Reticulum Stress and Oncomir-Associated Chemotherapeutic Drug Resistance Mechanisms in Breast Cancer Tumors
    (TUBITAK - The Scientific and Technological Research Council of Turkey, 2021) Mehdizadehtapeh, Leila; YERLİKAYA, PINAR OBAKAN
    Breast cancer, as a heterogenous malign disease among the top five leading causes of cancer death worldwide, is defined as by far the most common malignancy in women. It contributes to 25% of all cancer-associated deaths after menopause. Breast cancer is categorized based on the expression levels of cell surface and intracellular steroid receptors [estrogen, progesterone receptors, and human epidermal growth factor receptor (HER2)], and the treatment approaches frequently include antiestrogen, aromatase inhibitors, and Herceptin. However, the management and prevention strategies due to adverse side effects stress the patients. The unsuccessful treatments cause to raise the drug levels, leading to excessive toxic effects on healthy cells, and the development of multidrug-resistance (MDR) in the tumor cells against chemotherapeutic agents. MDR initially causes the tumor cells to gain a metastatic character, and subsequently, the patients do not respond adequately to treatment. Endoplasmic reticulum (ER) stress is one of the most important mechanisms supporting MDR development. ER stress-mediated chemotherapeutic resistance is very common in aggressive tumors. The in vitro and in vivo experiments on breast tumors indicate that ER stress-activated protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)- activating transcription factor (ATF4) signal axis plays an important role in the survival of tumors and metastasis. Besides, ER stress-associated oncogenic microRNAs (miRNAs) induce chemoresistance in breast tumors. We aimed to have a look at the development of resistance mechanisms due to ER stress as well as the involvement of ER stress-associated miRNA regulation following the chemotherapeutic regimen in the human breast tumors. We also aimed to draw attention to potential molecular markers and therapeutic targets.