Targeting cancer stemness mediated by BMI1 and MCL1 for non-small cell lung cancer treatment.
Erh-Hsuan LinJhen-Wei HsuTing-Fang LeeChiung-Fang HsuTsung-Hsien LinYi-Hua JanHsiang-Yi ChangChun-Ming ChengHui-Jan HsuWei-Wei ChenBo-Hung ChenHsing-Fang TsaiJung-Jung LiChi-Ying F HuangShih-Hsien ChuangJia-Ming ChangMichael HsiaoCheng-Wen WuPublished in: Journal of cellular and molecular medicine (2022)
Lung cancer is the leading cause of cancer-associated death, with a global 5-year survival rate <20%. Early metastasis and recurrence remain major challenges for lung cancer treatment. The stemness property of cancer cells has been suggested to play a key role in cancer plasticity, metastasis and drug-resistance, and is a potential target for drug development. In this study, we found that in non-small cell lung cancer (NSCLC), BMI1 and MCL1 play crucial roles of cancer stemness including invasion, chemo-resistance and tumour initiation. JNK signalling serves as a link between oncogenic pathway or genotoxicity to cancer stemness. The activation of JNK, either by mutant EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule, BI-44, was developed, which effectively suppressed BMI1/MCL1 expressions and inhibited tumour formation and progression in preclinical models. Targeting cancer stemness mediated by BMI1/MCL1 with BI-44 provides the basis for a new therapeutic approach in NSCLC treatment.
Keyphrases
- papillary thyroid
- body mass index
- stem cells
- small cell lung cancer
- small molecule
- epithelial mesenchymal transition
- squamous cell
- poor prognosis
- cell death
- cell therapy
- oxidative stress
- risk assessment
- single cell
- lymph node metastasis
- cancer therapy
- transcription factor
- long non coding rna
- young adults
- advanced non small cell lung cancer
- endoplasmic reticulum stress
- drug delivery
- human health
- chemotherapy induced