熱休克蛋白基因是一組在外界刺激下被誘導的基因群，且其蛋白質產物可將細胞內大多數受到損害的蛋白質適當的摺疊以維持其功能。根據其分子量通常可被細分為幾個家族。其中，熱休克蛋白70是最為重要的家族之一，由於其具抗細胞凋亡的能力，所以與癌細胞轉型息息相關。然而，熱休克蛋白70基因的調節及其蛋白抗細胞凋亡的機制並不十分清楚。因而促使我們進行本研究工作。
首先，本研究以抗癌藥膠達那黴素處理人類非小型肺癌細胞H460進行熱休克蛋白70家族的基因調節。利用電噴霧串聯質譜及北方墨漬法分析，發現熱休克蛋白70-1/2為此家族中主要被誘導的同質體。其中的轉錄活化也以膠體電泳位移分析獲得證實。再者，從激酶抑制劑的掃描分析中發現，蛋白質激酶C抑制劑可抑制熱休克蛋白70-1/2的誘導，也表示蛋白質激酶C可能參與熱休克蛋白70-1/2誘導的訊息傳遞。此外，膠達那黴素可短暫地引起細胞內鈣離子的增加，螯合細胞內的鈣離子或耗盡細胞內鈣離子的儲存也降低了熱休克蛋白70-1/2的誘導。因此，膠達那黴素可能透過鈣離子及蛋白質激酶C誘導熱休克蛋白70-1/2。
另一方面，熱休克蛋白70家族中的另一成員葡萄糖調控蛋白78可保護細胞免於在內質網逆境或DNA損壞時所產生的細胞凋亡。本研究亦發現葡萄糖調控蛋白78是H460細胞在內質網逆境中主要被誘導的蛋白質。然而，絲氨酸蛋白質水解酵素抑制劑AEBSF可使細胞在內質網逆境狀況抑制葡萄糖調控蛋白78的誘導、增加粒線體通透性及增加細胞凋亡。同時AEBSF也促進內質網逆境時Raf-1的降解並減少其磷酸化。親和性結合及胞器分離試驗結果亦顯示葡萄糖調控蛋白78與Raf-1同時存在粒線體外膜上。Raf-1的基質BAD磷酸化也在內質網逆境反應中增加，但是預處理AEBSF卻減少其磷酸化。此外，大量表達葡萄糖調控蛋白78或Raf-1使細胞減少內質網逆境產生的細胞凋亡。這些結果顯示葡萄糖調控蛋白78藉由保護Raf-1維持粒線體的通透性，進而減少內質網逆境引起的細胞凋亡。
綜言之，本研究發現熱休克蛋白70家族在基因調節上以及抗細胞凋亡的分子機制，相關研究成果可能貢獻於癌症的詳細分子機制及化療的新方向。

Heat shock proteins (HSPs) are a defined set of genes response to a variety of external stimuli and their products are mainly molecular chaperones that are crucially involved in the maintenance of the proper functions of a large range of intracellular proteins. The stress proteins are usually sub-classified a number of HSPs families according to their molecular weight. Among them, the HSP70s is one of the most important HSPs families and highly associated with tumor transformation because of its anti-apoptotic function. However, the detailed mechanisms of HSP70s in gene regulation and anti-apoptosis are not fully understood.
First of all, we examined gene regulation of HSP70s in geldanamycin (GA, a potent anti-cancer drug)-treated human non-small cell lung cancer H460 cells. In this study, we showed that the HSP70-1/2 are the major inducible forms under GA treatment using LC-ESI-MS/MS and Northern blotting analysis. Transactivation of HSP70-1/2 was further determined by electrophoretic mobility-shift assay using heat shock element as a probe. The signaling pathway mediators involved in HSP70-1/2 transactivation were screened by the kinase inhibitor scanning technique. The protein kinase C (PKC)-specific inhibitor Ro-31-8425 and the Ca2+-dependent PKC inhibitor Gö-6976 diminished GA-induced HSP70-1/2, suggesting an involvement of the PKC in the process. Moreover, GA treatment causes a transient increase of intracellular Ca2+. Chelating intracellular Ca2+ with BAPTA-AM or depletion of intracellular Ca2+ store with A23187 or thapsigargin significantly decreased GA-transactivated HSP70-1/2 expression. Taken together, our results demonstrated that GA induces specific HSP70-1/2 isoforms expression in H460 cells through signaling pathway mediated by Ca2+ and PKC.
On the other hand, the chaperone glucose-regulated protein 78 (GRP78), a member of HSP70s, protects cells from cytotoxicity induced by DNA damage or endoplasmic reticulum (ER) stress. In this study, we showed that GRP78 is a major inducible protein in H460 cells treated with ER stress inducers including A23187 and thapsigargin. 4-[2-aminoethyl]-benzenesulfonyl fluoride hydrochloride (AEBSF), an inhibitor of serine protease, diminished GRP78 induction, enhanced mitochondrial permeability and augmented apoptosis in H460 cells during ER stress. Simultaneously, AEBSF promoted Raf-1 degradation and decreased phosphorylation level of Raf-1 at Ser338 and/or Tyr340 during ER stress. His-tag affinity pull-down assay and subcellular fractionation results also demonstrated that GRP78 associateed and colocalized with Raf-1 on the outer membrane of mitochondria. Treatment of cells with ER stress inducers inactivated Bcl-XL/Bcl-2-associated death promoter (BAD) by phosphorylation at Ser75, which is a phosphorylation site by Raf-1. Nevertheless, AEBSF attenuated phosphorylation of BAD leading to cytochrome c release from mitochondria. Additionally, overexpression of GRP78 and/or Raf-1 protected cells from ER stress-induced apoptosis. These results indicate that GRP78 may chaperone Raf-1 to maintain mitochondrial permeability and thus protects cells from ER stress-induced apoptosis.
Taken together, we discovered that molecular mechanisms of HSP70s in gene regulation and anti-apoptotic function. These findings might provide a possible pharmacological manipulation for cancer exposed to chemotherapy.

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