肝醣合成酶激酶-3 (glycogen synthase kinase-3; GSK-3) 是細胞中的一種絲氨酸/蘇氨酸激酶，對於細胞分化、增殖及凋亡有重要的調控。愈來愈多的研究指出GSK-3與癌症之間的關係，但關於它在血液腫瘤方面的角色並沒有明確的報導。本論文將探討GSK-3在血癌中扮演的凋亡角色。論文中的結果將可提供GSK-3調控血癌細胞走向凋亡的分子機轉，並且提供血癌治療策略上的啟發。論文第一部份為探索GSK-3所媒介之抗血癌作用。諸多血癌用藥已被報導透過誘導內質網壓力 (endoplasmic reticulum stress; ER stress) 進而造成細胞凋亡，因此我以血癌細胞株建立了一個由ER stress所誘導的凋亡模式，在這個細胞模式中檢視GSK-3所媒介之凋亡路徑及訊息傳遞。我的結果指出利用ER stress誘劑tunicamycin (抑制蛋白質醣化作用) 可以在人類血癌細胞株U937及HL-60引發凋亡，主要的凋亡路徑是透過活化GSK-3β，進而誘導其下游硫胱氨酸天門冬胺酸蛋白酶-2 (caspase-2) 活化，caspase-2可引發溶小體不穩定，進而釋出其內部的硫胱胺酸蛋白酶B (cathepsin B) 進入細胞質，cathepsin B可以調控caspase-8及caspase-3的活化，使細胞走向凋亡。然而在帶有Bcr-Abl的慢性骨髓性血癌 (chronic myeloid leukemia; CML) 細胞株K562中，tunicamycin無法誘導GSK-3的活化以及其下游的凋亡路徑，因此我假設在K562細胞中，GSK-3的較難活化可能是引起凋亡抗性的原因，我進而合併給予已知可活化GSK-3 的藥物，發現此方法確實可以促進K562細胞對於ER stress造成之凋亡的感受性。這些結果暗示著GSK-3在抗血癌治療上是重要的凋亡調控蛋白，因此，在論文第二部份，我進一步去證實活化GSK-3是否可成為新的血癌治療策略。CML是一種由bcr-abl融合基因所造成的血液腫瘤，這個融合基因轉譯出之融合蛋白Bcr-Abl可以透過其酪胺酸激酶 (tyrosine kinase) 的活性來促進血癌細胞高度增殖及存活優勢。我發現在K562細胞中表達持續活化的GSK-3β，可以減緩細胞的增殖，並且抑制Bcr-Abl可以活化GSK-3並引起GSK-3媒介之細胞凋亡，這些結果指出活化GSK-3可以負向調控Bcr-Abl的訊息傳遞。我們過去的研究曾指出一種具有腫瘤抑制活性的鞘脂類脂質(sphingolipid)－神經醯胺 (ceramide) 具有活化GSK-3的特性，因此我嘗試利用葡萄糖腦苷脂合成酶 (glucosylceramide synthase) 抑制劑PDMP來累積細胞當中的ceramide進而活化GSK-3，用以促進現行CML的治療。合併PDMP的處理可以增強Bcr-Abl抑制劑所引發之GSK-3活化及細胞凋亡。我也將此合併治療用在具抗藥性的CML細胞株Ba/F3-p210T315I中，這個細胞的Bcr-Abl帶有T315I點突變，又稱為守門員點突變 (gatekeeper mutation)，在目前CML治療上，T315I點突變所引起的抗藥性是最強也最難治療的，我發現，無論是在細胞及動物實驗中，Bcr-Abl抑制劑及PDMP合併給予可以顯著性地誘導Ba/F3-p210T315I細胞走向凋亡，進而我也收集了二個帶有T315I點突變的CML病人，以他們的血癌細胞進行體外合併藥物處理，也發現顯著的凋亡誘導效果。Bcr-Abl抑制劑及PDMP合併所產生的致敏效果是透過ceramide累積及Bcr-Abl去活化進而引發GSK-3所調節之細胞凋亡。綜合以上結果，我提供了在血癌中一個由GSK-3所調控之凋亡路徑，並且也進一步建議累積ceramide可以用於克服CML對於治療藥物的抗性。

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which possesses multiple regulatory roles on cell differentiation, proliferation, and apoptosis. Accumulating studies have implicated GSK-3 in cancer. However, the role of GSK-3 in hematopoietic malignancy is not well understood. This thesis is aimed at examining the apoptotic role of GSK-3 in leukemia. The results may provide insights into the mechanisms by which GSK-3 regulates apoptosis in leukemia and may suggest potential therapeutic strategies. In the first part of this thesis, the GSK-3-mediated anti-leukemic actions were explored. Since various anti-leukemic agents have been reported to exert their apoptotic ability through induction of endoplasmic reticulum (ER) stress, I established a model of ER stress-induced apoptosis using leukemic cell lines to check the apoptotic signaling pathways regulated by GSK-3. Results showed that ER stressor tunicamyin, a protein glycosylation inhibitor, can induce apoptosis in human monocytic leukemia/lymphoma U937 and acute myeloid leukemia HL-60 cells. The apoptotic signaling is mainly through GSK-3β activation followed by caspase-2-mediated lysosomal membrane permeabilization (LMP). LMP leads to lysosomal destabilization and cause cathepsin B relocation from the lysosome to the cytosol. Activated cathepsin B mediates caspase-8 and caspase-3 activation followed by apoptosis. However, in Bcr-Abl-positive chronic myeloid leukemia (CML) K562 cells, tunicamycin failed to activate GSK-3 as well as subsequent apoptotic pathways. I therefore hypothesized that inactivation of GSK-3 in K562 cells might contribute to apoptosis resistance. Pharmacologic manipulation to activate GSK-3 sensitized K562 cells to ER stress-induced apoptosis. For anti-leukemia therapy, these data suggest GSK-3 as an important regulator in triggering apoptosis. Therefore, in the second part of this thesis, I further verified the concept of activating GSK-3 as a new anti-leukemic strategy. CML is a hematopoietic malignancy caused by the presence of bcr-abl fusion gene which encodes a potent oncoprotein Bcr-Abl. Bcr-Abl promotes cell hyper-proliferation and confers pro-survival advantages through its tyrosine kinase activity. In K562 cells, I showed that activating GSK-3β caused growth inhibition. Inhibiting Bcr-Abl also activated GSK-3 to promote apoptosis. The data indicated that GSK-3 activation negatively regulated Bcr-Abl signaling. Our previous study showed a tumor suppressor sphingolipid ceramide is a potent GSK-3 activator. Therefore, using a glucosylceramide synthase inhibitor PDMP, I tried to accumulate endogenous ceramide to activate GSK-3 to enhance the efficacy of current CML therapy. Combining PDMP enhanced Bcr-Abl inhibitor-induced GSK-3 activation and apoptosis. I further tested the efficacy of Bcr-Abl inhibitor/PDMP combination in drug resistant cells which carried T315I gatekeeper mutation on the Bcr-Abl kinase domain. The T315I mutation is now the most drug-resistant and problematic mutation in clinical management of CML. Of note, combining Bcr-Abl inhibitor with PDMP significantly induced apoptosis in Ba/F3-p210T315I cells in vitro and in vivo and in primary cells from two CML T315I patients. The sensitization effect occurs through ceramide accumulation and Bcr-Abl inactivation followed by GSK-3-dependent apoptosis. Taken together, these data provide a GSK-3-initiated pathway in leukemia apoptosis and further suggest accumulating ceramide as a potential therapeutic strategy to overcome emerging drug resistance in CML treatment.

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