Melis Kartal Yandim

Major apoptotic mechanisms and genes involved in apoptosis

As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer.

Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDP-glucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

STAT pathway in the regulation of zoledronic acid-induced apoptosis in chronic myeloid leukemia cells

In this study, we aimed to evaluate the cytotoxic and apoptotic effects of zoledronic acid on K562 chronic myeloid leukemia (CML) cells and to examine the roles of STAT genes on zoledronic acid-induced apoptosis. The results showed that zoledronic acid decreased proliferation, and induced apoptosis in K562 cells in a dose- and time-dependent manner. mRNA and protein levels of STAT3, -5A and -5B genes were significantly reduced in zoledronic acid-treated K562 cells. These data indicated that STAT inhibition by zoledronic acid may be therapeutic in CML patients following the confirmation with clinical studies.

Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line

The Forkhead box protein M1 (FoxM1) is an important transcription factor having significant roles in various cellular events. FoxM1 overexpression has been reported to be related with many types of cancer. However, it is not known whether it contributes to oncogenesis of acute lymphoblastic leukemia. Siomycin A, a thiazol antibiotic, is known to inhibit FoxM1 transcriptional activity. In this study, we aimed to determine gene expression levels of FoxM1 in Jurkat cells (T-cell acute lymphoblastic leukemia cell line) and therapeutic potential of targeting FoxM1 by siomycin A alone and in combination with dexamethasone which improves the survival of children with T-cell acute lymphoblastic leukemia (ALL). We also examined the molecular mechanisms of siomycin A and dexamethasone-induced cell death in Jurkat cells. We demonstrated that FoxM1 mRNA is highly expressed in Jurkat cells. Dexamethasone and siomycin A caused a significant reduction in gene expression levels of FoxM1 in Jurkat cells. Targeting FoxM1 by siomycin A and dexamethasone caused a significant decrease in T-ALL cell line proliferation through induction of G1 cell cycle arrest. All these findings suggest a possible role of FoxM1 in T-cell ALL pathogenesis and represent FoxM1 as an attractive target for T-cell ALL therapy.

A minimally invasive transfer method of mesenchymal stem cells to the intact periodontal ligament of rat teeth: a preliminary study

The aim of this study was to introduce a minimally invasive procedure for mesenchymal stem cell (MSC) transfer into the intact periodontal ligament (PDL) of the molar teeth in rats. Ten 12-week-old Wistar albino rats were used for this preliminary study. MSCs were obtained from bones of two animals and were labeled with green fluorescent protein (GFP). Four animals were randomly selected for MSC injection, while 4 animals served as a control group. Samples were prepared for histological analysis, Cox-2 mRNA expression polymerase chain reaction analysis, and fluorescent microscopy evaluation. The number of total cells, number of osteoclastic cells, and Cox-2 mRNA expression levels of the periodontal tissue of teeth were calculated. The number of total cells was increased with MSC injections in PDL significantly (P < 0.001). The number of osteoclastic cells and Cox-2 mRNA expression were found to be similar for the two groups. GFP-labeled MSCs were observed with an expected luminescence on the smear samples of the PDL with transferred MSCs. The results of this preliminary study demonstrate successful evidence of transferring MSCs to intact PDL in a nonsurgical way and offer a minimally invasive procedure for transfer of MSCs to periodontal tissues.