Browsing by Author "Can, A."

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    Apoptotic vascular smooth muscle cell depletion via BCL2 family of proteins in human ascending aortic aneurysm and dissection
    (Blackwell Publishing Ltd, 2012) Durdu, S.; Deniz, G. C.; Balci, D.; Zaim, C.; Dogan, A.; Can, A.; Akcali, K. C.; Akar, A. R.
    Aims: This study investigates the expression patterns of BCL2 (B-cell CLL/lymphoma2) family of proteins and the extent of vascular smooth muscle cell (VSMC) apoptosis in thoracic aortic aneurysms (TAA), type-A aortic dissections (TAD), and nondilated ascending aortic samples. Methods: Aortic wall specimens were obtained from patients undergoing surgical repair for TAA (n = 24), TAD (n = 20), and normal aortic tissues from organ donors (n = 6). The expression pattern of BCL2, BCL2L1 (BCL2-like1), BAK1 (BCL2-antagonist/killer1), and BAX (BCL2-associated X protein) proteins was investigated by immunohistochemistry. Furthermore, colocalization of alpha smooth muscle actin (ACTA2) and caspase3 (CASP3) in aortic VSMCs was analyzed by double-immunofluorescence staining. Onset of DNA fragmentation was measured by TUNEL assay. Results: Apoptotic index was significantly increased in both TAD group (31.3 ± 17.2, P < 0.001) and TAA group (21.1 ± 12.7, P = 0.001) relative to control aortas (2.0 ± 1.2). Anti-CASP3 and ACTA2 double-immunostaining confirmed apoptosis in VSMCs in TAA and TAD groups but not in controls. Proapoptotic BAX expression was significantly elevated in VSMCs of TAA patients, compared with that of controls (OR = 20; P = 0.02; 95% CI, 16-250). In contrast, antiapoptotic BCL2L1 expression was higher in controls compared with that of TAA group (OR = 11.2; P = 0.049; 95% CI, 1.0-123.9). Furthermore, BAX/BCL2 ratio was significantly increased in both TAA (1.2 ± 0.7, P < 0.001) and TAD (0.6 ± 0.4, P = 0.05) groups relative to controls (0.2 ± 0.1, P < 0.001). Conclusions: Apoptotic VSMC depletion in human TAA/TAD is associated with disturbance of the balance between proapoptotic and antiapoptotic members of the BCL2 family proteins, which may have a role in the pathogenesis of vascular remodelling in aortic disease. In light of the future studies, targeting apoptotic pathways in TAA and TAD pathogenesis may provide therapeutic benefits to patients by slowing down the progression and even possibly preventing the TAD. © 2012 Blackwell Publishing Ltd.
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    ItemOpen Access
    Imetelstat (a telomerase antagonist) exerts off target effects on the cytoskeleton
    (2013) Mender I.; Senturk, S.; Ozgunes, N.; Can Akcali, K.; Kletsas, D.; Gryaznov, S.; Can, A.; Shay J.W.; Dikmen, Z.G.
    Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. Imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. Currently, GRN163L is being investigated in several clinical trials, including a phase II human non small cell lung cancer clinical trial, in a maintenance setting following standard doublet chemotherapy. In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length. This leads to the loss of cell adhesion properties; however, the mechanism underlying this effect is not yet fully understood. In the present study, we observed that GRN163L treatment leads to the loss of adhesion in A549 lung cancer cells, due to decreased E-cadherin expression, leading to the disruption of the cytoskeleton through the alteration of actin, tubulin and intermediate filament organization. Consequently, the less adherent cancer cells initially cease to proliferate and are arrested in the G1 phase of the cell cycle, accompanied by decreased matrix metalloproteinase-2 (MMP-2) expression. These effects of GRN163L are independent of its telomerase catalytic activity and may increase the therapeutic efficacy of GRN163L by decreasing the adhesion, proliferation and metastatic potential of cancer cells in vivo.
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    Role of FLT3 and its potential interaction partner, Hsp27 in hepatocellular carcinoma
    (Elsevier, 2012-04) Aydın, Muammer Merve; Bayın, N. S.; Akhan, Ece; Can, A.; Akçalı, Kamil Can
    Regeneration ability of liver is known to be associated with the activation of resident oval cells. Previously our group showed that oval cell marker, FLT3 changes its cellular localization in response to partial hepatectomy and suggested a role in liver regeneration. In addition, FLT3 was shown to play an important role in cellular proliferation and activation of PI3K and Ras. Hsp27 on the other hand, is a small chaperone that has roles in the inhibition of apoptosis and overexpressed in a wide range of cancers increasing their metastatic potential. Due to the role of FLT3 in liver regeneration and cellular proliferation, we aimed to analyze the effect of FLT3 in hepatocellular carcinoma (HCC) both in vitro and in vivo and its interaction with Hsp27.