內質網靶向藥物L-硒胱胺酸破壞蛋白質平衡並誘導大腸直腸癌細胞發生免疫原性細胞死亡

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王傑民(Chieh-Min Wang) 查詢紙本館藏

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生命科學系

論文名稱

內質網靶向藥物L-硒胱胺酸破壞蛋白質平衡並誘導大腸直腸癌細胞發生免疫原性細胞死亡
(ER-targeting agent L-selenocystine sabotages proteostasis and induces immunogenic cell death in colorectal carcinoma)

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至系統瀏覽論文 (2029-7-4以後開放)

摘要(中)

腫瘤細胞於腫瘤微環境中面臨各式壓力，如氧化壓力、缺氧和營養物質缺乏等，這些壓力可能會破壞蛋白質平衡並導致內質網壓力(ER stress)發生。為了存活，腫瘤細胞必須活化相應的訊息傳導途徑以抵抗壓力，例如在許多固體腫瘤中有觀察到活化的未折疊蛋白反應（unfolded protein response, UPR），得以幫助腫瘤細胞紓解壓力並促進存活。然而， UPR 活化雖有助於腫瘤細胞在輕度或中度 ER stress下恢復，但過於嚴重或持久的 ER stress反而會引發細胞程序性死亡，如細胞凋亡(apoptosis)或類凋亡(paraptosis)。在腫瘤細胞中，ER stress誘導之paraptosis被認為是一種免疫原性ex細胞死亡（immunogenic cell death, ICD），其透過釋放Damage-associated molecular patterns（DAMPs）和細胞因子(cytokines)來激發抗腫瘤免疫能力。藉由增加腫瘤細胞的ER stress，使之超過可承受閾值進而誘導ICD發生，是一種具有前景的癌症治療策略。硒元素已被證明能誘導多種癌細胞產生ER stress和細胞凋亡而不會傷害非癌細胞，這使得含硒化合物成為合適的潛在化療藥物。然而，硒元素對癌細胞及非癌細胞的相異反應，以及硒介導的ER stress在誘導ICD中的作用仍不明確。
於此研究中，我們探討L-硒胱胺酸（SeC）對大腸直腸癌（CRC）細胞和非大腸直腸癌細胞的影響。我們的研究結果表明，SeC 處理使得IRE1途徑活化並誘導了CRC 細胞發生ER stress介導的細胞凋亡，並且這些情形在非CRC 細胞中沒有發生。CRC 細胞中，IRE1敲落加劇了SeC誘導之細胞死亡，表明在嚴重的ER stress下的細胞死亡仍有其他途徑參調控。 SeC 透過活性氧介導(ROS-mediated)機制抑制了 CRC 細胞中蛋白酶體的活性，導致多泛素化(ubiquitinated)蛋白的累積。此外，SeC 還促進了 ICD 因子的釋放、造成 ER 形態改變，並誘導了廣泛的細胞質空洞化(extensive cytoplasmic vacuolization)，這些現象表明蛋白質平衡遭受破壞並發生paraptosis，從而可能激發抗腫瘤免疫反應。經過SeC 處理的 CRC 細胞中，其ER衍生囊泡內的硒元素含量增加，且ER區域性的 ROS 增加，這意味著 SeC 可能在進入細胞後直接進入並干擾 ER。我們的研究結果為SeC 的選擇性抗癌分子機制提供了見解，並對SeC 在癌症治療中的精準應用提供前瞻指引。

摘要(英)

Tumor cells face various microenvironmental stresses, such as oxidative stress and deprivation of oxygen and nutrients, which could disrupt protein homeostasis and induce endoplasmic reticulum (ER) stress. To survive, tumor cells must activate adaptive pathways, including the upregulation of unfolded protein response (UPR) observed in many solid tumors, which helps resolve stress and promote survival. While UPR activation aids tumor cells in the recovery of mild or moderate ER stress, severe or prolonged ER stress can instead trigger programmed cell death, e.g. apoptosis or paraptosis. In tumor cells, ER stress-induced paraptosis is regarded as a form of immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) and cytokines that stimulate anti-tumor immunity. Inducing ICD by surpassing tumor cells’ ER stress threshold emerges as a promising cancer treatment strategy. Selenium (Se) has been shown to induce ER stress and apoptosis in many cancer types without harming non-cancerous cells, rendering selenium-containing compounds potential chemotherapeutic agents. However, the differential impacts of Se on cancer versus non-cancerous cells, and the role of Se-mediated ER stress in ICD induction, remain poorly understood.
In this study, we investigated the effects of L-selenocystine (SeC) on colorectal cancer (CRC) cells compared to non-CRC cells. Our findings demonstrated that SeC treatment activated the IRE1 pathway and induced ER stress-mediated apoptosis in CRC cells, but not non-CRC cells. IRE1 knockdown exacerbated SeC-induced cell death in CRC cells, suggesting alternative pathways contributing to cell death under severe ER stress. SeC inhibited proteasome activity via ROS-mediated mechanisms in CRC cells, leading to polyubiquitinated protein accumulation. Moreover, SeC promoted the release of ICD factors, altered ER morphology, and induced extensive cytoplasmic vacuolization, indicating disruption of protein homeostasis and induction of paraptosis, which could enhance anti-tumor immune responses. Elevated selenium contents within the ER-derived vesicles and ER-localized ROS in SeC-treated CRC cells implied direct ER perturbation by SeC. Our findings provide insights into the molecular mechanisms underlying the selective anti-cancer effects of SeC, offering prospects for its precise application in cancer therapy.

關鍵字(中)

★ 硒
★ 硒胱胺酸
★ 內質網壓力
★ 蛋白質平衡
★ 類凋亡
★ 免疫原性細胞死亡

關鍵字(英)

★ selenium
★ selenocystine
★ endoplasmic reticulum stress
★ proteostasis
★ paraptosis
★ immunogenic cell death

論文目次

中文摘要 i
Abstract iii
Acknowledgment v
Abbreviations ix
I. Introduction 1
I.1. Role of chemotherapy in colorectal cancer treatment 1
I.2. Selenium 2
Selenocystine 3
I.3. Endoplasmic reticulum stress and unfolded protein response 3
Inositol-requiring enzyme 1 (IRE1) pathway 4
Protein kinase RNA-like ER kinase (PERK) pathway 4
C/EBP homologous binding protein (CHOP) 5
I.4. Proteostasis 6
Ubiquitin-proteasome system 7
I.5. Paraptosis 8
I.6. Immunogenic cell death 8
II. Objective Aims 10
III. Materials and Methods 11
III.1. Materials 11
Cell lines 11
Reagents and chemicals 11
Antibodies 15
Primer sequences 16
III.2. Methods 18
Cell culture 18
Selenocystine preparation 18
Protein extraction and Western blotting 18
Proteasome activity assay 19
Glutathione ratio detection assay 20
Cell viability assay 20
Intracellular ROS determination 21
Apoptosis assay 21
Fluorescent imaging 21
siRNA transfection 22
RNA extraction and quantitative real-time reverse transcription PCR 22
Microsome purification 23
Cryo-soft X-ray tomography 24
Statistical analysis 24
IV. Results 26
IV.1. SeC induced ROS-mediated and apoptotic cell death in CRC cells 26
IV.2. SeC provoked unrecoverable ER stress in CRC cells 27
IV.3. IRE1 pathway protects cells from SeC-induced ER stress 28
IV.4. SeC sabotaged protein degradation in CRC cells 28
IV.5. SeC accumulated in ER and increased ER-localized ROS in CRC cells 29
IV.6. SeC induces paraptosis and upregulates ICD cytokines in CRC cells 30
V. Figures 33
Figure 1. SeC induced oxidative stress and cell death in CRC cells but not in non-CRC cells. 38
Figure 2. SeC induced ER stress and hampered pro-survival signals in CRC cells. 42
Figure 3. Silencing IRE1 aggravated cell death under SeC treatment. 44
Figure 4. SeC inhibited proteasome activity in CRC cells, to an accumulation of poly-ubiquitinated proteins. 46
Figure 5. Increased selenium levels and ER-localized ROS were observed in WiDr cells after SeC treatment. 50
Figure 6. SeC disrupted ER structure and induced cytoplasmic vacuolization as well as the expression of ICD factors in WiDr cells, but not in CCD841-CoN cells. 55
Figure 7. Graphical summary and conclusion 56
VI. Discussion 57
VI.1. Fate of cell under ER stress—Survival or death 57
VI.2. Role of IRE1 activation under ER stress 58
VI.3. Immunogenic cell death in cancer therapy 59
VI.4. The potential mechanisms of SeC-import 60
VII. Conclusion 63
VIII. Future prospects 65
IX. Appendix 67
X. References 73

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指導教授

羅月霞(Yueh-Hsia Luo)

審核日期

2024-7-19

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