Journal Article

Olanzapine suppresses mPFC activity-norepinephrine releasing to alleviate CLOCK-enhanced cancer stemness under chronic stress

Yang, Yuqing, He, Bin, Wang, Xu, Luo, Huandong, Liu, Quentin, Wang, Chunli, Peng, Fei, Zhang, Xiaoyu, Wang, Ling, Cui, Bai, Lv, Dekang, Liu, Congcong, Zhao, Zhuoran, Wang, Cenxin, Lu, Jinxin, Su, Keyu, Kelley, Keith W., Meng, Peixuan, Liu, Xianxian

2024

Overview

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 LSL−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 Kras LSL−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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenosine / Adenoviruses / Animals / Anxiety / Anxiety - drug therapy / Biomedical and Life Sciences / Brain / Brain tumors / Cancer / Cancer stemness / Cancer therapies / Carcinogenesis - drug effects / Cell Biology / Cell culture / Cell Line, Tumor / Chemical properties / Chemoresistance / Chemotherapy / Cholecystokinin / Chronic stress / Circadian rhythm / CLOCK Proteins - genetics / CLOCK Proteins - metabolism / CLOCK transcription / Cyclic adenylic acid / Cyclic AMP response element-binding protein / Cyclic AMP Response Element-Binding Protein - metabolism / Cytokines and Growth Factors / Depression - drug therapy / Depression, Mental / Development and progression / Dopamine / Drug therapy / Ethylenediaminetetraacetic acid / Experiments / Gemcitabine / Gemcitabine resistance / Genetic aspects / Health aspects / Humans / Kinases / Life Sciences / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - pathology / Male / Medical research / Mental depression / Mice / Mice, Inbred C57BL / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Noradrenaline / Norepinephrine / Norepinephrine - metabolism / Olanzapine / Olanzapine - pharmacology / Open-field behavior / Pemetrexed / Physiological aspects / Product enhancement / Protein kinase A / Protein-Ligand Interactions / Receptors / Stress / Stress (Psychology) / Stress, Psychological - complications / Stress, Psychological - drug therapy / Testing / Transcription activation / Tumor cell lines / Tumor cells / Tumorigenesis / Tumors