23. Ulusal Biyokimya Kongresi Ãzel SayÄ±sÄ± - TÃ¼rk Biyokimya Dergisi

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XXIII. ULUSAL B‹YOK‹MYA KONGRES‹ 29 Kasım - 2 Aralık 2011 Hilton Hotel - Adana 23. Ulusal Biyokimya Kongresi, Adana [23 rd National Biochemistry Congress, Adana / TURKEY] İÇİNDEKİLER PROF. DR. İNCİ ÖZER ANISINA KONFERANS İYON KANALLARININ KANSERDEKİ İŞLEVSEL ROLÜ: YENİ GELİŞMELER CONFERENCE IN MEMORY OF PROF. DR. İNCİ ÖZER THE FUNCTIONAL ROLE OF ION CHANNELS IN CANCER : NEW DEVELOPMENTS CONTENTS DAVETLİ KONUŞMACI ÖZETLERİ Mustafa B A DJAMGOZ Imperial College Londra, İngiltere Kanser hucrelerinde cesitli iyon kanallari bulunmakta, ve bu kanallarin aktivitesi erken baslangictan ileri evre metastaza kadar bircok farkli kanser asamasina etki etmektedir. Kanallarin farkli ekspresyon dagilimlari, primer ve sekonder kanser olusumunun degisik sekillerde kontrol edildigi kavramina da uygunluk gostermektedir. Yeni konsept – Celex hipotezi Solid tumorlerden elde edilen kanitlar gostermektedir ki: 1) primer tumor olusumu temel olarak K+ kanali aktivitesi ile idare edilmektedir; (2) sekonder tumor olusumu (metastaz) voltaj bagimli Na+ kanallarinin (VBNK) islevsel olarak artmasi ile ilerletilmektedir; ve (3) VBNK artisina voltaj bagimli K+ kanallarinin (VBKK) azalmasi eslik etmekte ve bu durum metastatik hucre zarlarini elektriksel olarak uyarilabilir hale getirmektedir. Biz, 2. ve 3. maddelere birarada “Celex hipotezi” adini veriyoruz. Buna gore, agresif (metastatik) tumorlerin karakteristik ozelligi olan hiperaktif/cevresine dusman davranisini arttiran etkenin, hucre zarinin uyarilabilirligi oldugunu dusunuyoruz. Bugune kadar, VBNK artisi (ve eger test edildi ise beraberindeki VBKK azalisi) insanlardaki meme, prostat, kolon, akciger (farkli cesitleri), yumurtalik ve rahim agizi kanserlerinde bulunmustur. Ozellikle dikkate deger bir calismada, House ve arkadaslari [Cancer Res (2010) 70, 6957- 6967] bir VBNK geni olan SCN5A’nin insanlardaki kolon kanserinde “anahtar” duzenleyici rolu oldugunu ortaya koymuslardir. Kanser VBNK’lerinin molekuler yapisi Biz VBNK’lerin molekuler yapisini meme ve prostat kanserlerinde calistik, ve gosterdik ki sorumlu olan kanal tipleri, memede SCN5A (Nav1.5) ve prostatta SCN9A’dir (Nav1.7). Onemli olan nokta sudur ki, her iki durumda da kanallarin neonatal (gelisimsel olarak kontrol edilen) tipi ekspres edilmektedir; baska bir degisle kanserdeki VBNK ekspresyonu bir “onko-fotal” fenomendir. Bu durum, kanser hucrelerinin/dokularinin de-diferansiye olmus (tekrar farklilasmis) dogasiyla da uyumludur. Bu karakteristik ozellik, VBNK’lerin yetiskin ve Mustafa B A DJAMGOZ Imperial College London, UK A variety of ion channels are expressed in cancer cells and channel activity contributes to several different aspects / stages of cancer, from early initiation to late-stage metastatic progression. The expression patterns adhere to the notion that primary and secondary tumourigenesis are controlled differently. New concept - Celex hypothesis The evidence from a range of solid tumours, taken together, suggests: 1) that primary tumourigenesis is driven primarily by K+ channel activity (various types); (2) that secondary tumourigenesis (metastasis) is promoted by functional upregulation of voltage-gated Na+ channels (VGSCs); and (3) that the VGSC upregulation is accompanied by downregulation of voltage-gated K+ channels (VGPCs), thereby rendering metastatic cancer cell membranes electrically excitable. We refer to (2) and (3) combined as the “Celex hypothesis” ie that it is the membrane excitability that enhances the cells’ hyperactive / unsociable behaviour, characteristic of aggressive (metastatic) tumours. To date, VGSC upregulation (and the concomitant VGPC downregulation, where studied) have been found in human cancers of breast, prostate, colon, lung (various forms), ovary and cervix. In a particularly remarkable recent study House et al. [Cancer Res (2010) 70, 6957-6967] concluded that the VGSC gene SCN5A is a “key” (in fact, ‘master’) regulator of human colon cancer. Molecular nature of the cancer VGSCs We have studied the molecular nature of the VGSCs in breast and prostate cancer and found the ‘culprits’ to be SCN5A (Nav1.5) and SCN9A (Nav1.7). Importantly, in both cases, it is the neonatal (developmentally regulated) splice form that is expressed, i.e. VGSC expression in cancer is an “oncofoetal” phenomenon, in line with the dedifferentiated nature of cancer cells/tissues. This characteristic implies that cancer cells may be directly targetable by agents that distinguish between adult and neonatal forms of VGSCs. Association of ion channels with mainstream cancer mechanisms ABSTRACTS OF INVITED LECTURES Turk J Biochem, 2011; 36 (S2) http://www.TurkJBiochem.com
XXIII. ULUSAL B‹YOK‹MYA KONGRES‹ 29 Kasım - 2 Aralık 2011 Hilton Hotel - Adana 23. Ulusal Biyokimya Kongresi, Adana [23 rd National Biochemistry Congress, Adana / TURKEY] İÇİNDEKİLER DAVETLİ KONUŞMACI ÖZETLERİ neonatal tiplerini ayirdedebilen ajanlar kullanarak kanser hucrelerinin dogrudan hedef alinabilecegi olasiligina isaret etmektedir. İyon kanallarinin baslica kanser mekanizmalari ile olan baglantisi VBNK’lerin de dahil oldugu iyon kanallari, baslica kanser mekanizmalari ile derinden baglantilidir. Bu mekanizmalar arasinda, kontrol edici steroit hormonlar ve buyume faktorleri (upstream) ile Ca2+ sinyalleri ve pH kontrolu (downstream) bulunmaktadir. Iyon kanallari ve kanser hedefleri Neonatal Nav1.5 pek cok farkli sekillerde hedef alinabilir: 1) Nav1.5’e ozgun antikor; (2) Nav1.5 uzerindeki D1:S3-S4 splice bolgesindeki aminoasit farkliliklarini temel alarak tasarlanan kucuk molekuller; ve (3) Nav1.5’in hipoksi ile artan persistent akim bilesenine karsi blokorler. Yakin zamandaki gelismeler gostermektedir ki, bu uc yaklas birbirinden bagimsiz olarak mumkundur. Ion channels, including VGSCs, are intimately associated with mainstream mechanisms of cancer. Such mechanisms include regulatory steroid hormones and growth factors (upstream) and Ca2+ signalling and pH regulation (downstream). Ion channels as cancer targets Neonatal Nav1.5 can be targeted in a number of ways: 1) Nav1.5-specific antibody; (2) small-molecules based upon the amino acid differences in the spliced D1:S3-S4 region of Nav1.5; (3) blockers of the hypoxia-enhanced persistent current component of Nav1.5. Recent progress suggests that all three approaches are independently possible. CONTENTS ABSTRACTS OF INVITED LECTURES Turk J Biochem, 2011; 36 (S2) http://www.TurkJBiochem.com
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23. Ulusal Biyokimya Kongresi Ãzel SayÄ±sÄ± - TÃ¼rk Biyokimya Dergisi

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23. Ulusal Biyokimya Kongresi Ãzel SayÄ±sÄ± - TÃ¼rk Biyokimya Dergisi