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Olanzapine suppresses mPFC activity-norepinephrine releasing to alleviate CLOCK-enhanced cancer stemness under chronic stress.
Lu, Jinxin; Zhang, Xiaoyu; Su, Keyu; Luo, Huandong; Liu, Congcong; Yang, Yuqing; He, Bin; Wang, Cenxin; Zhao, Zhuoran; Liu, Xianxian; Wang, Xu; Meng, Peixuan; Lv, Dekang; Wang, Chunli; Kelley, Keith W; Wang, Ling; Cui, Bai; Liu, Quentin; Peng, Fei.
Afiliación
  • Lu J; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Zhang X; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
  • Su K; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Luo H; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Liu C; Department of Oncology, the First Affiliated Hospital of Dalian Medical University, Dalian, China.
  • Yang Y; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • He B; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Wang C; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Zhao Z; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Liu X; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Wang X; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Meng P; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Lv D; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Wang C; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Kelley KW; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Wang L; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • Cui B; Department of Pathology, College of Medicine, Department of Animal Sciences, College of ACES, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Liu Q; Department of Oncology, the First Affiliated Hospital of Dalian Medical University, Dalian, China. wangling@firsthosp-dmu.com.
  • Peng F; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. cuibai@dmu.edu.cn.
Cell Commun Signal ; 22(1): 375, 2024 Jul 25.
Article en En | MEDLINE | ID: mdl-39054537
ABSTRACT

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:

KrasLSL-G12D/WT 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 KrasLSL-G12D/WT 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Norepinefrina / Olanzapina Límite: Animals / Humans / Male Idioma: En Revista: Cell Commun Signal Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Norepinefrina / Olanzapina Límite: Animals / Humans / Male Idioma: En Revista: Cell Commun Signal Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido