探討熱休克蛋白27表現於癌細胞膜上之機制

Abstract

熱休克蛋白（Heat shock proteins， HSPs）是一類功能性相關蛋白質，當細胞受到升高溫度或其他壓力時它們的表達就會增長。在受到環境壓力時，易造成蛋白質失去作用，而這些廣泛存在於真核與原核細胞中的HSPs被認為能幫助穩定蛋白質的結構，來維持蛋白質的活性。和其它大分子HSP一樣，small heat shock protein-Hsp27也具有molecular chaperones的功能，能夠防止未折疊的蛋白質形成無法恢復的聚合。且發現許多腫瘤細胞內也會大量表現Hsp27增加細胞對熱及氧化壓力產生抗性及抑制細胞的計畫性死亡(apoptosis)。一些活體外的實驗證實，Hsp27會被磷酸化，且磷酸化的程度影響Hsp27聚合及chaperone活性。然而本研究發現Hsp27不只過度表現於腫瘤細胞之內，也會表現於腫瘤細胞的細胞膜外，而在正常細胞之細胞膜外Hsp27表限量相當的低甚至是不表現。其所參與的機制為何，目前並沒有相關之報導。本研究發現PKC-□與NF-□B細胞訊號傳遞路徑,透過磷酸化Hsp27 serine 15,參與Hsp27膜外表現負調控角色，當Hsp27 serine 15磷酸化，Hsp27膜外表現下降，反之Hsp27 serine 78的磷酸化能夠促進Hsp27膜外表現。

Stress or heat shock proteins (HSPs) are the most conserved proteins present in both prokaryotes and eukaryotes. Their expressions are induced in response to a wide of physiological and environmental insults. Intracellular heat shock protein (Hsp) 27 is ubiquitously expressed in various cell types and is involved in actin polymerization, and inhibition of mitochondrial apoptosis. Recent researches show that Heat shock proteins (Hsps) are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. In cancer cells, the expression of Hsp27 is abnormally high, and Hsp27 may participate in oncogenesis and in chemoresistance. In addition, current research has shown that Hsp 27 were located in the cytoplasm or nucleus. In this study, we found that Hsp27 is overexpressed on outer surface of human cancer cells but not normal human cells. However, the mechanisms of Hsp27 translocation to cancer cell surface are not defined yet. Our results suggest that PKC-□ and NF-κB signaling pathway negative mediated Hsp27 translocation to cancer cell surface by phosphorylation at Hsp27 serine 15. Moreover, HSP27 only when phosphorylated at serine 78 were overexpression on the cell surfaces.