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Received for publication, April 24, 2003

Inhibition of Transcription Factor Stat5. Induces Cell Death. of. Human Prostate. Cancer Cells*. Received for publication, April 24, 2003 Published, JBC Papers in Press, April 28, 2003, DOI 10.1074/jbc.M304307200.

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Received for publication, April 24, 2003

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  1. Inhibition of Transcription Factor Stat5 Induces Cell Death of Human Prostate Cancer Cells* Received for publication, April 24, 2003 Published, JBC Papers in Press, April 28, 2003, DOI 10.1074/jbc.M304307200 Tommi J. Ahonen‡§¶, Jianwu Xie‡¶, Matthew J. LeBaron‡, Jianqiong Zhu‡, Martti Nurmi , Kalle Alanen**, Hallgeir Rui‡, and Marja T. Nevalainen‡‡‡ 班級:生科四甲 學生:梁育銘

  2. 男性泌尿生殖系統構造圖

  3. 症狀 • 早期的攝護腺癌是沒有症狀的。當攝護腺癌侵犯到尿道時, 病患會 有頻尿、夜尿、尿急、尿流細小、尿道疼痛和血尿等症狀, 和良性 攝護腺肥大的症狀類似。當攝護腺癌轉移到骨骼, 如腰椎骨時, 就 會造成腰背疼痛以神經痛的症狀。

  4. Introduction 攝護腺癌常見於 50 歲以上的男性。在美國僅次於肺癌 及大腸 癌，是男性常見的癌病，美國 的罹患率是每十萬人口有七千人（或 者說每六個美國男性就有一人，在一 生當中會罹患此病），以 1995 年為例， 在所有該年新檢測出的癌症之中，攝 護腺癌就佔了 36%。每年有 240,000個新的病例被檢出，並造成超過四萬人的死亡。

  5. Abstract 從40個病患身上所取得的攝護腺腫瘤組織切片,在其樣本中我們發現大約26個人(65%),它的Stat5有異常活化的現象,因此作者大膽假設異常活化的Stat5和攝護腺腫瘤有一定的關係,所以它提出阻斷Stat5的功能可能是一種治療攝護腺腫瘤的一個新方法。

  6. STATs蛋白質簡介: STATs蛋白質的發現,最早是由於干擾素的研究,由於INF刺激細胞後,會產生一群特定基因的表現,而發現這些基因的表現,是需要STATs蛋白質的參與作用,STATs 蛋白質它擁有兩種生物功能: 1.將訊息由細胞表面傳到細胞核內 2.STATs蛋白質也參與其基因表現調控

  7. STATs Family的成員有七個: STATs Family: 包括STAT1. STAT2…..到STAT6,除了STAT2 .STAT6較大,大約是850個amino acids,其它大約是 700-800個amino acids ,然後STAT5它有兩個同源性的基因產物分別是 STAT5a- 94-kDa (Tyr-694) STAT5b- 92-kDa (Tyr-699) JAK2

  8. STAT3 Signaling Pathway

  9. 名詞介紹 Ad- adenovirus 為一個DNA腫瘤病毒,可做為真核細胞基因表現之研究 DNStat5- dominant-negative Stat5 顯性-抑制型的Stat5,為Stat5的一個mutant,喪失其活化功能 AdDNStat5-Adenoviral gene delivery of a dominant-negative Stat5 STAT-Signal transducer and activator of transcription

  10. Materials 從40個病人身上所取得的攝護腺腫瘤組識切片 1.CWR22Rv 2.LNCap 3.Pc-3 cells

  11. Human prostate cancer cells Anti-phospho-TyrStat5 Anti-pan-Stat5

  12. Normal human prostate epithelium Anti-phospho-TyrStat5

  13. A dose-dependent effect on cell viability of adenoviral gene delivery of a dominant-negative Stat5 mutant (AdDNStat5)

  14. Morphology of cell death induced by AdDNStat5 in CWR22Rv and LnCap cells ( 72h , 8 m.o.i) ( 96h , 32 m.o.i)

  15. Dose-dependent expression of WTStat5 or DNStat5 in CWR22Rv and LnCap cells

  16. DNA fragmentation analyzed by nucleosomal ELISA after exposure to AdDNStat5, AdWTStat5,AdlacZ, AdCtrl, or mock infection in CWR22Rv and LNCap 0.4 0.3 2.1 2.4 ( 72h , 32m.o.i) ( 48h , 8 m.o.i)

  17. 用 Flow Cytometry 測量細胞 DNA含量和細胞的大小,來檢測凋亡細胞

  18. DNStat5-induced cell apoptosis involved caspase-3 activation ( 48h , 32 m.o.i) ( 36h , 8 m.o.i)

  19. DNStat5- induced caspase-3 activation is associated with activation of caspase-9.

  20. 結論 用原位偵測法去測定磷酸化和細胞核的Stat5,在大部份我們檢測的攝護腺腫瘤細胞發現它的Stat5是活化的,所以我們提出如果抑制Stat5的活化可以是一種新的基因療法,它可以廣泛應用在治療攝護腺腫瘤細胞上,我們觀察到CWR22Rv和LNCap這 兩個腫瘤細胞中,阻斷Stat5的活化可以引發一連串的反應,如caspase-3caspase-9 和的活化最後誘導整過攝護腺腫瘤細胞apoptosis,來達到治療腫瘤的效果.

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