ABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplastic Stem Cells/metabolism , Polycomb Repressive Complex 1/genetics , Polycomb Repressive Complex 1/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
In the present study, laser Doppler measurement was used to quantitatively investigate the microcirculatory effects of contact pressure stimulation (PS) underneath the Hoku acupoint and its nearby nonacupoint, to improve the understanding of the mechanisms underlying acupressure therapy. A control group (no PS applied) and three experimental groups with different applied PS (group A, 60 mmHg on the Hoku acupoint; group B, 60 mmHg on a nearby nonacupoint; group C, 50 mmHg on a nearby nonacupoint) were studied. Each experiment involved recording data of a 20 min baseline and two periods of effects after stopping PS. The relative energy contribution (REC) in five frequency bands, as revealed by Morlet wavelet transformation, was calculated. At the pressed site, the average value of the laser Doppler flux signal was increased only in group A, and coefficient of variance of the amplitude sequence was only significantly decreased during measurement (M1: 0 to 20 min) in group B. The RECs of the myogenic-related band were significantly increased in groups A and C, whereas there were no significant changes found in group B. The improved microcirculatory blood-flow perfusion at Hoku may partly explain why acupressure can exert better therapeutic effects than PS applied to other sites. The laser Doppler spectra responses illustrated that the induced pressure-induced vasodilation can be attributed mainly to the myogenic response. Laser Doppler measurement and analysis therefore represent a noninvasive method of examining the microcirculatory efficacy of acupressure therapy.
