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Olanzapine suppresses mPFC activity-norepinephrine releasing to alleviate CLOCK-enhanced cancer stemness under
Jinxin Lu1,2, Xiaoyu Zhang1, Keyu Su1,3
1Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
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.
Insights
Olanzapine (OLZ) reverses chronic stress-induced lung tumorigenesis and chemoresistance by suppressing the mPFC-NE-CLOCK axis. This intervention reduces anxiety-like behaviors and cancer stemness, offering a novel therapeutic strategy.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Chronic stress exacerbates cancer development through neuro-endocrine pathways.
- The precise mechanisms by which brain-body interactions influence stress-induced tumorigenesis are not fully understood.
- Olanzapine (OLZ) is known to reverse anxiety associated with chronic stress.
Purpose of the Study:
- To investigate the effect of Olanzapine (OLZ) on chronic stress-induced lung tumorigenesis and cancer stemness.
- To elucidate the underlying brain-body interaction mechanisms involving neuro-endocrine activation.
- To assess OLZ's impact on anxiety-like behaviors and chemo-sensitivity in lung cancer models.
Main Methods:
- Utilized KrasLSL-G12D/WT and LLC1 syngeneic lung cancer models.
- Assessed cancer stemness markers via qPCR, western-blotting, immunohistology, and flow cytometry.
- Evaluated anxiety-like behaviors using elevated plus maze and open field tests; depression-like behaviors via tail suspension test.
- Human anxiety and depression assessed using the Hospital Anxiety and Depression Scale (HADS).
- Chemo-sensitivity evaluated in vivo and in vitro.
Main Results:
- Olanzapine (OLZ) reversed chronic stress-enhanced lung tumorigenesis in both models.
- OLZ alleviated anxiety and depression-like behaviors by suppressing mPFC neuro-activity and reducing norepinephrine (NE) release.
- NE activates the ADRB2-cAMP-PKA-CREB pathway, promoting CLOCK transcription and cancer stemness.
- CLOCK deficiency or OLZ reversed NE/chronic stress-induced gemcitabine resistance.
- Tumoral CLOCK expression correlated with stress, NE levels, and poor prognosis in lung cancer patients.
Conclusions:
- Olanzapine (OLZ) ameliorates chronic stress-induced tumorigenesis and chemoresistance via a novel mechanism.
- OLZ suppresses the mPFC-NE-CLOCK axis, reversing stress-induced anxiety-like behaviors and lung cancer stemness.
- Reduced NE release inhibits the ADRB2-cAMP-PKA-CREB pathway, decreasing CLOCK transcription and overcoming chemoresistance.
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