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NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung
Brian Madajewski1,2, Michael A Boatman2, Ivan Martinez2
1Memorial Sloan Kettering-Cornell Center for Translation of Cancer Nanomedicine, Memorial Sloan Kettering Cancer Center, 415 East 68th Street, New York, NY 10065, USA.
Abstract:
Identifying cellular drivers responsible for enhancing cancer cell resistance to therapeutics provides critical information for designing more effective drugs. Populations of slowly growing, self-renewing, chemo-resistant cells purportedly contribute to the development of therapeutic resistance in many solid tumors. In the current study, we implemented a tumor spheroid model to determine whether NAD(P)H quinone oxidoreductase-1 (NQO1) was requisite for self-renewal and promotion of the drug-resistant phenotype in non-small cell lung cancer (NSCLC). We found that stable depletion of NQO1 in A549 and H358 human NSCLC tumor models inhibits self-renewal capabilities, as demonstrated by a reduced ability to form primary, secondary, and tertiary spheroids. In contrast, the rescue of NQO1 expression restored the tumor cells' ability to form spheroids. Additionally, we discovered that NQO1 depletion renders cisplatin-refractory tumor spheroids highly susceptible to drug treatment. Together, these results suggest that NQO1 loss reduces the self-renewing capabilities of NSCLC cells and enhances their susceptibility to clinically relevant therapeutics. These findings describe a novel role for NQO1 and suggest that combining NQO1-inhibitors with conventional chemotherapeutics may enhance anti-tumor effects.
Insights
NAD(P)H quinone oxidoreductase-1 (NQO1) loss impairs non-small cell lung cancer self-renewal and drug resistance. Inhibiting NQO1 may enhance chemotherapy effectiveness against lung tumors.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Chemo-resistant cancer cells contribute to therapeutic failure in solid tumors.
- Self-renewing, slow-cycling cells are implicated in maintaining tumor heterogeneity and resistance.
- NAD(P)H quinone oxidoreductase-1 (NQO1) is a potential regulator of cancer cell phenotypes.
Purpose of the Study:
- To investigate the role of NQO1 in self-renewal and drug resistance in non-small cell lung cancer (NSCLC).
- To determine if NQO1 is essential for maintaining chemo-resistant phenotypes in NSCLC.
Main Methods:
- Utilized a tumor spheroid model with human NSCLC cell lines (A549, H358).
- Assessed self-renewal capacity by quantifying spheroid formation (primary, secondary, tertiary).
- Examined the effect of NQO1 depletion and re-expression on spheroid formation and drug susceptibility.
Main Results:
- Stable depletion of NQO1 significantly inhibited self-renewal capabilities in NSCLC spheroids.
- Restoration of NQO1 expression rescued the spheroid formation capacity.
- NQO1-depleted, cisplatin-refractory spheroids exhibited increased susceptibility to drug treatment.
Conclusions:
- NQO1 plays a critical role in maintaining the self-renewing and drug-resistant properties of NSCLC cells.
- Loss of NQO1 function enhances the sensitivity of NSCLC cells to chemotherapy.
- Targeting NQO1 in combination with conventional chemotherapeutics presents a potential strategy to improve anti-tumor efficacy.
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