奥氮平抑制 mPFC 活动-去甲肾上腺素释放，以减轻慢性应激下 CLOCK 增强的癌症干性。
Olanzapine suppresses mPFC activity-norepinephrine releasing to alleviate CLOCK-enhanced cancer stemness under chronic stress.
机构信息
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
出版信息
Cell Commun Signal. 2024 Jul 25;22(1):375. doi: 10.1186/s12964-024-01747-y.
BACKGROUND
Olanzapine (OLZ) reverses chronic stress-induced anxiety. Chronic stress promotes cancer development via abnormal neuro-endocrine activation. However, how intervention of brain-body interaction reverses chronic stress-induced tumorigenesis remains elusive.
METHODS
Kras lung cancer model and LLC1 syngeneic tumor model were used to study the effect of OLZ on cancer stemness and anxiety-like behaviors. Cancer stemness was evaluated by qPCR, western-blotting, immunohistology staining and flow-cytometry analysis of stemness markers, and cancer stem-like function was assessed by serial dilution tumorigenesis in mice and extreme limiting dilution analysis in primary tumor cells. Anxiety-like behaviors in mice were detected by elevated plus maze and open field test. Depression-like behaviors in mice were detected by tail suspension test. Anxiety and depression states in human were assessed by Hospital Anxiety and Depression Scale (HADS). Chemo-sensitivity of lung cancer was assessed by in vivo syngeneic tumor model and in vitro CCK-8 assay in lung cancer cell lines.
RESULTS
In this study, we found that OLZ reversed chronic stress-enhanced lung tumorigenesis in both Kras lung cancer model and LLC1 syngeneic tumor model. OLZ relieved anxiety and depression-like behaviors by suppressing neuro-activity in the mPFC and reducing norepinephrine (NE) releasing under chronic stress. NE activated ADRB2-cAMP-PKA-CREB pathway to promote CLOCK transcription, leading to cancer stem-like traits. As such, CLOCK-deficiency or OLZ reverses NE/chronic stress-induced gemcitabine (GEM) resistance in lung cancer. Of note, tumoral CLOCK expression is positively associated with stress status, serum NE level and poor prognosis in lung cancer patients.
CONCLUSION
We identify a new mechanism by which OLZ ameliorates chronic stress-enhanced tumorigenesis and chemoresistance. OLZ suppresses mPFC-NE-CLOCK axis to reverse chronic stress-induced anxiety-like behaviors and lung cancer stemness. Decreased NE-releasing prevents activation of ADRB2-cAMP-PKA-CREB pathway to inhibit CLOCK transcription, thus reversing lung cancer stem-like traits and chemoresistance under chronic stress.
背景
奥氮平（OLZ）可逆转慢性应激引起的焦虑。慢性应激通过异常的神经内分泌激活促进癌症发展。然而，大脑-身体相互作用的干预如何逆转慢性应激引起的肿瘤发生仍然难以捉摸。
方法
使用 Kras 肺癌模型和 LLC1 同基因肿瘤模型研究 OLZ 对癌症干性和焦虑样行为的影响。通过 qPCR、western-blotting、免疫组织化学染色和干性标志物的流式细胞术分析评估癌症干性，通过小鼠连续稀释肿瘤发生和原发性肿瘤细胞的极限稀释分析评估癌症干性样功能。通过高架十字迷宫和旷场试验检测小鼠的焦虑样行为。通过悬尾试验检测小鼠的抑郁样行为。通过医院焦虑和抑郁量表（HADS）评估人类的焦虑和抑郁状态。通过体内同基因肿瘤模型和肺癌细胞系的体外 CCK-8 测定评估肺癌的化疗敏感性。
结果
在这项研究中，我们发现 OLZ 逆转了 Kras 肺癌模型和 LLC1 同基因肿瘤模型中慢性应激增强的肺肿瘤发生。OLZ 通过抑制 mPFC 中的神经活动并减少慢性应激下去甲肾上腺素（NE）的释放来缓解焦虑和抑郁样行为。NE 激活 ADRB2-cAMP-PKA-CREB 途径促进 CLOCK 转录，导致癌症干性样特征。因此，CLOCK 缺陷或 OLZ 逆转了 NE/慢性应激诱导的肺癌中吉西他滨（GEM）耐药。值得注意的是，肿瘤 CLOCK 表达与肺癌患者的应激状态、血清 NE 水平和预后不良呈正相关。
结论
我们确定了一种新的机制，即 OLZ 改善慢性应激增强的肿瘤发生和化疗耐药性。OLZ 抑制 mPFC-NE-CLOCK 轴逆转慢性应激引起的焦虑样行为和肺癌干性。减少 NE 释放可防止 ADRB2-cAMP-PKA-CREB 途径的激活，从而抑制 CLOCK 转录，从而逆转慢性应激下的肺癌干性样特征和化疗耐药性。
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