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

• Published in: Cell communication and signaling Vol. 22; no. 1; pp. 375 - 17
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 25.07.2024; BioMed Central; BMC
• Subjects: Adenosine; Adenoviruses; Animals; Anxiety; Anxiety - drug therapy; Brain; Brain tumors; Cancer; Cancer stemness; Cancer therapies; Carcinogenesis - drug effects; 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; Depression - drug therapy; Depression, Mental; Development and progression; Dopamine; Drug therapy; Ethylenediaminetetraacetic acid; Experiments; Gemcitabine; Gemcitabine resistance; Genetic aspects; Health aspects; Humans; Kinases; 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; Stress; Stress (Psychology); Stress, Psychological - complications; Stress, Psychological - drug therapy; Testing; Transcription activation; Tumor cell lines; Tumor cells; Tumorigenesis; Tumors; China; Chronic stress; Olanzapine; CLOCK transcription; mPFC activity; Cancer stemness; Norepinephrine; Gemcitabine resistance
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-024-01747-y

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. 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. 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. 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.