Cancer Cell Adhesion and Signaling
Zehra Tavşan, PhD Student
Deniz Erkan, PhD Student
Sebila Balta, MSc Student
Emery Shami, MSc Student
Ayşegül Kırma, Undergraduate Student
Buse Akgün, MSc, Visiting Student
Cell adhesion molecules not only allow the cells to interact with their neighbors and with the underlying extracellular matrix via heteromeric protein complexes but also transmit information to the cell interior about the environment, such as the presence of neighboring cells or the type and composition of the extracellular matrix. So, changes in the expression of cell-adhesion molecules affect not only the adhesive repertoire of a cell but also its signal-transduction status. Conversely, signaling pathways can modulate the function of cell-adhesion molecules, altering the interactions between cells and their environment. Recent experimental evidence indicates that such processes have a crucial role in tumor progression, in particular during invasion and metastasis. PKCs have been shown to regulate a variety of biological events, including cell–cell and cell–extracellular matrix adhesion. PKC represents a family of at least 12 lipid-dependent serine/threonine kinases, which are differentially expressed in various tissues and play distinct roles in several signal transduction pathways which regulate a wide variety of cellular stimuli.
One of the key candidate messengers involved in PKC-mediated signaling is the reactive oxygen species (ROS). The oxidative stress due to the endogenous production of ROS is normally counteracted by endogenous antioxidant systems that most mammalian cells have developed. When the antioxidant machinery is overwhelmed by ROS production, the resulting oxidative damage can lead to cell death. Cancer usually manifests late in life and could be due to an increase in ROS production or decrease in ROS removal or both. ROS have been well implicated in cell proliferation, inhibition of apoptosis, or mutagenesis, and its high level contributes to the development of cancer. Therefore, cell’s internal environment also plays a big role in the carcinogenesis.
Our main research interest is in the area of signal transduction in carcinogenesis. Our laboratory investigates the intracellular pathways that contribute to malignant transformation and metastatic dissemination of cancer cells in various models, including colon and ovarian cancer. The core focus of my group is on the relationship between cell adhesion molecule expression, cell signaling and cell fates such as apoptosis and autophagy. There are two main research interests that are studying in our projects:
1) in vivo link of cell adhesion molecules and PKCs located in TEMs to the development of two major human cancers, colon and ovarian:
- A growing body of evidence indicates that alterations in the adhesion properties of cells play a pivotal role in the development and progression of cancer. PKCs especially are involved in the phosphorylation of cell adhesion molecules, and can directly change cell adhesion dynamic that promotes tumor progression and also supports apoptosis resistance. Our challenge is to elucidate such complex signaling mechanism with the ultimate goal of finding novel targeting molecules for cancer diagnosis and treatment.
- Small molecule inhibitors of PKC isozymes as anti-cancer drug candidates: Research in my laboratory is focused on the discovery of new anti-tumor drugs to decipher cellular signaling networks with an emphasis on PKCs.
2) Involvement of ROS and oxidative stress in cancer
Most cancer cells exhibit elevated oxidative stress with increased metabolic activity and production of ROS. The main goal is to study at the molecular level how does the cell sense oxidative stress and which mechanisms are triggered to allow adaptation to the stress. We, therefore, are trying to identify and characterize the components and mechanisms which activate signal transduction pathways to respond to oxidative stress in the colon and ovarian cancer.
Cell adhesion molecules take part in intercellular and cell-extracellular matrix interactions of cancer. Cancer progression is a multi-step process in which some adhesion molecules play a pivotal role in the development of recurrent, invasive, and distant metastasis. A growing body of evidence indicates that alterations in the adhesion properties of neoplastic cells play a pivotal role in the development and progression of cancer. Epithelial cell adhesion molecule (EpCAM) was initially discovered as a cell-surface antigen highly expressed in a variety of carcinomas. In our previous work, we identified EpCAM acts as a potent inhibitor of novel protein kinase C (nPKC) in cancer cells via a short segment of the EpCAM cytoplasmic tail. We showed that the loss of EpCAM causes sequentially a strong overstimulation of PKC activity and of the Erk pathway, leading to exacerbated myosin contractility, loss of cadherin-mediated adhesion, tissue dissociation, and, ultimately, cell death.
Ayar-Kayalı lab is currently seeking highly motivated graduate and PhD students. If interested, please contact firstname.lastname@example.org
Full list and citations: Google Scholar: Hulya Ayar Kayali
• Maghzal N, Kayali HA, Rohani N, Kajava AV, Fagotto F., EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC, Developmental Cell, 27 (3), 263–277, 2013.
• Tavsan, Z., & Kayali, H. A. . The Variations of Glycolysis and TCA Cycle Intermediate Levels Grown in Iron and Copper Mediums of Trichoderma harzianum. Applied biochemistry and biotechnology, 176(1), 76-85, 2015