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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Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/94735

Title:	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
Authors:	王傑民;Wang, Chieh-Min
Contributors:	生命科學系
Keywords:	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;selenium;selenocystine;endoplasmic reticulum stress;proteostasis;paraptosis;immunogenic cell death
Date:	2024-07-19
Issue Date:	2024-10-09 15:27:07 (UTC+8)
Publisher:	國立中央大學
Abstract:	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。 ;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.
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