Open AccessTargeting cancer stemness mediated by BMI1 and MCL1 for non‐small cell lung cancer treatment
Author(s) -
Lin ErhHsuan,
Hsu JhenWei,
Lee TingFang,
Hsu ChiungFang,
Lin TsungHsien,
Jan YiHua,
Chang HsiangYi,
Cheng ChunMing,
Hsu HuiJan,
Chen WeiWei,
Chen BoHung,
Tsai HsingFang,
Li JungJung,
Huang ChiYing,
Chuang ShihHsien,
Chang JiaMing,
Hsiao Michael,
Wu ChengWen
Publication year - 2022
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.17453
Subject(s) - bmi1 , lung cancer , cancer , cancer research , cancer stem cell , metastasis , mcl1 , medicine , cancer cell , biology , oncology , downregulation and upregulation , biochemistry , gene
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.