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Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a
Zhimin Tang1, Yilan Zhang2, Zhengyi Yu2
1Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
Abstract:
Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.
Insights
Metformin suppresses cancer stemness in paclitaxel-resistant lung cancer by activating FOXO3a, a tumor suppressor. This process involves AMP-activated protein kinase (AMPK) and inhibits pathways like Akt and MEK.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cancer stem cells (CSCs) drive drug resistance and metastasis in non-small-cell lung cancer (NSCLC).
- Forkhead box O3a (FOXO3a) functions as a tumor suppressor, but its role in CSCs remains under investigation.
- Paclitaxel (PTX) resistance in NSCLC is often associated with enhanced stem-like properties.
Purpose of the Study:
- To investigate the role of FOXO3a in mediating metformin's inhibitory effects on cancer stemness in PTX-resistant NSCLC cells.
- To elucidate the molecular mechanisms by which metformin targets CSCs, focusing on the FOXO3a pathway.
Main Methods:
- Induction of PTX resistance in NSCLC cells to generate CSC-like phenotypes.
- Manipulation of FOXO3a expression (knockdown and overexpression) in sensitive and resistant cells.
- Treatment with metformin and assessment of stemness markers, self-renewal, and tumorigenesis in vitro and in vivo.
- Pharmacological inhibition of key signaling pathways (AMPK, Akt, MEK) to dissect metformin's mechanism.
Main Results:
- Chronic PTX exposure induced CSC-like features and FOXO3a inactivation.
- FOXO3a overexpression suppressed stemness and tumorigenesis in PTX-resistant NSCLC cells.
- Metformin reduced CSC self-renewal and stemness markers, upregulated FOXO3a, and activated AMPK.
- Metformin's effects were dependent on FOXO3a and AMPK activation, and involved inhibition of Akt and MEK signaling.
Conclusions:
- FOXO3a acts as a crucial tumor suppressor in PTX-resistant NSCLC, inhibiting stemness.
- Metformin effectively suppresses CSC stemness by activating the AMPK/FOXO3a axis and inhibiting Akt/MEK pathways.
- Targeting the FOXO3a pathway presents a potential therapeutic strategy against drug-resistant NSCLC.
