Researcher: Gözüaçık, Devrim
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Gözüaçık, Devrim
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Publication Metadata only Autophagy as a key cellular stress response mechanism(Wiley, 2021) Gözüaçık, Devrim; Faculty Member; School of Medicine; 40248N/APublication Metadata only Antitumor efficacy of ceranib-2 with nano-formulation of PEG and rosin esters(Humana Press Inc, 2021) Ben Taleb, Ali; Karakus, Selcan; Tan, Ezgi; Ilgar, Merve; Kutlu, Ozlem; Kutlu, Hatice Mehtap; Kilislioglu, Ayben; N/A; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248Ceranib-2 is a recently discovered, poorly water-soluble potent ceramidase inhibitor, with the ability to suppress cancer cell proliferation and delay tumor growth. However, its poor water solubility and weak cellular bioavailability hinder its use as a therapeutic agent for cancer. PEGylated rosin esters are an excellent platform as a natural polymer for drug delivery applications, especially for controlling drug release due to their degradability, biocompatibility, capability to improve solubility, and pharmacokinetics of potent drugs. In this study, stable aqueous amphiphilic submicron-sized PEG400-rosin ester-ceranib-2 (PREC-2) particles, ranging between 100 and 350 nm in a 1:1 mixture, were successfully synthesized by solvent evaporation mediated by sonication. Conclusion: Stable aqueous PEGylated rosin ester nanocarriers might present a significant solution to improve solubility, pharmacokinetic, and bioavailability of ceranib-2, and hold promises for use as an anticancer adjacent drug after further investigations.Publication Metadata only Comparative analysis of autophagy in drug responses and aggressive behavior of adult versus pediatric glioma cell lines(Wiley, 2022) Aygun, Bera; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; Yenidoğan, İrem; Peker, Nesibe; Deveci, Gamze; Kırmızı, Döndü; Asarcıklı, Fikret; Sözmen, Banu Oflaz; Akyoldaş, Göktuğ; Kulaç, İbrahim; Solaroğlu, İhsan; Erbey, Mehmet Fatih; Gözüaçık, Devrim; Researcher; Researcher; PhD Student; Other; Doctor; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Faculty Member; N/A; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; School of Medicine; N/A; Graduate School of Health Sciences; N/A; N/A; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; Koç University Hospital; N/A; N/A; N/A; N/A; N/A; 327591; N/A; N/A; N/A; N/A; 198711; 203677; 102059; 206213; 40248Central nervous system tumors are the most common solid cancer and a leading cause of cancer-related deaths in children. Glioma is the most challenging pediatric CNS tumor with therapy resistance and poor prognosis in pediatric patients. Although histopathological analyses revealed similarities with adult brain glioma, emerging evidence suggests that the deregulated molecular pathways in pediatric glioma (p-GM) are different from that of adults. Autophagy, a cellular clearance system and a drug resistance mechanism, has been implicated in glioma progression, invasion, and relapse, yet its role in pediatric patients is not well documented. In this study, we compared the autophagic capacity of adult versus p-GM cell lines and evaluated the effect of autophagy manipulation on drug responses. In addition, migration, extracellular matrix invasion ability, and the metabolism of pediatric and adult gliomas were compared and the contribution of autophagy to the aggressive phenotype was evaluated.Publication Metadata only Autophagy as a key cellular mechanism in health and disease(Wiley, 2022) N/A; Gözüaçık, Devrim; Faculty Member; School of Medicine; 40248N/APublication Metadata only Autophagy and hepatic tumor microenvironment associated dormancy(Springer, 2021) N/A; N/A; Akkoç, Yunus; Gözüaçık, Devrim; Researcher; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; School of Medicine; N/A; 40248The goal of successful cancer treatment is targeting the eradication of cancer cells. Although surgical removal of the primary tumors and several rounds of chemo- and radiotherapy reduce the disease burden, in some cases, asymptomatic dormant cancer cells may still exist in the body. Dormant cells arise from the disseminated tumor cells (DTCs) from the primary lesion. DTCs escape from immune system and cancer therapy and reside at the secondary organ without showing no sign of proliferation. However, under some conditions. dormant cells can be re-activated and enter a proliferative state even after decades. As a stress response mechanism, autophagy may help the adaptation of DTCs at this futile foreign microenvironment and may control the survival and re-activation of dormant cells. Studies indicate that hepatic microenvironment serves a favorable condition for cancer cell dormancy. Although, no direct study was pointing out the role of autophagy in liver-assisted dormancy, involvement of autophagy in both liver microenvironment, health, and disease conditions has been indicated. Therefore, in this review article, we will summarize cancer dormancy and discuss the role and importance of autophagy and hepatic microenvironment in this context.Publication Metadata only Complex pattern formation in solutions of protein and mixed salts using dehydrating sessile droplets(Amer Chemical Soc, 2020) Pathak, Binita; Christy, John; Sefiane, Khellil; N/A; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248A sessile droplet of a complex fluid exhibits several stages of drying leading to the formation of a final pattern on the substrate. We report such pattern formation in dehydrating droplets of protein (BSA) and salts (MgCl2 and KCl) at various concentrations of the two components (protein and salts) as part of a parametric study for the understanding of complex patterns of dehydrating biofluid droplets (blood and urine), which will eventually be used for diagnosis of bladder cancer. The exact analysis of the biofluid patterns will require a rigorous parametric study; however, the current work provides an initial understanding of the effect of the basic components present in a biofluid droplet. Arrangement of the protein and the salts, due to evaporation, leads to the formation of some very distinctive final structures at the end of the droplet lifetime. Furthermore, these structures can be manipulated by varying the initial ratio of the two components in the solution. MgCl2 forms chains of crystals beyond a threshold initial concentration of protein (>3 wt %). However, the formation of such a crystal is also limited by the maximum concentration of the salt initially present in the droplet (<= 1 wt %). On the other hand, KCl forms dendritic and rectangular crystals in the presence of BSA. The formation of these crystals also depends on the relative concentration of salt and protein in the droplet. We also investigated the dried-out patterns in dehydrating droplets of mixed salts (MgCl2 + KCl) and protein. The patterns can be tuned from a continuous dendritic structure to a snow-flake type structure just by altering the initial ratio of the two salts in the mixture, keeping all other parameters constant.Publication Metadata only Cancer recurrence and omics: metabolic signatures of cancer dormancy revealed by transcriptome mapping of genome-scale networks(Mary Ann Liebert, Inc, 2022) Kutay, Merve; Çakır, Tunahan; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activity/inactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysis/gluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valine/leucine/isoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular. This work does not include any human subjects. We used data from literature, and they were cell-line data. Therefore, we do not have any IRB or Clinical Registration.Publication Metadata only Tumor-derived CTF1 (cardiotrophin 1) is a critical mediator of stroma-assisted and autophagy-dependent breast cancer cell migration, invasion and metastasis(Taylor & Francis, 2023) Dalci, Kubilay; Karakas, Hacer Ezgi; Erbil-Bilir, Secil; Yalav, Orcun; Sakman, Gurhan; Celik, Faruk; Arikan, Soykan; Zeybek, Umit; Ergin, Melek; Akkiz, Hikmet; Dengjel, Joern; Dogan-Ekici, A. Isin; N/A; Gözüaçık, Devrim; Akkoç, Yunus; Dilege, Ece; Faculty Member; Researcher; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; N/A; School of Medicine; Koç University Hospital; 40248; N/A; 218050Macroautophagy/autophagy is an evolutionarily conserved cellular stress response mechanism. Autophagy induction in the tumor microenvironment (stroma) has been shown to support tumor metabolism. However, cancer cell-derived secreted factors that initiate communication with surrounding cells and stimulate autophagy in the tumor microenvironment are not fully documented. We identified CTF1/CT-1 (cardiotrophin 1) as an activator of autophagy in fibroblasts and breast cancer-derived carcinoma-associated fibroblasts (CAFs). We showed that CTF1 stimulated phosphorylation and nuclear translocation of STAT3, initiating transcriptional activation of key autophagy proteins. Additionally, following CTF1 treatment, AMPK and ULK1 activation was observed. We provided evidence that autophagy was important for CTF1-dependent ACTA2/alpha-SMA accumulation, stress fiber formation and fibroblast activation. Moreover, promotion of breast cancer cell migration and invasion by activated fibroblasts depended on CTF1 and autophagy. Analysis of the expression levels of CTF1 in patient-derived breast cancer samples led us to establish a correlation between CTF1 expression and autophagy in the tumor stroma. In line with our in vitro data on cancer migration and invasion, higher levels of CTF1 expression in breast tumors was significantly associated with lymph node metastasis in patients. Therefore, CTF1 is an important mediator of tumor-stroma interactions, fibroblast activation and cancer metastasis, and autophagy plays a key role in all these cancer-related events.Publication Open Access Autophagy and cancer dormancy(Frontiers, 2021) Akçay, Arzu; Akkoç, Yunus; Peker, Nesibe; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; N/A; N/A; 40248Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called "dormancy" for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.Publication Open Access Crosstalk between autophagy and DNA repair systems(TÜBİTAK, 2021) Demirbağ Sarıkaya, Sinem; Çakır, Hatice; Gözüaçık, Devrim; Akkoç, Yunus; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248; N/AAutophagy and DNA repair are two essential biological mechanisms that maintain cellular homeostasis. Impairment of these mechanisms was associated with several pathologies such as premature aging, neurodegenerative diseases, and cancer. Intrinsic or extrinsic stress stimuli (e.g., reactive oxygen species or ionizing radiation) cause DNA damage. As a biological stress response, autophagy is activated following insults that threaten DNA integrity. Hence, in collaboration with DNA damage repair and response mechanisms, autophagy contributes to the maintenance of genomic stability and integrity. Yet, connections and interactions between these two systems are not fully understood. In this review article, current status of the associations and crosstalk between autophagy and DNA repair systems is documented and discussed.