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Abstract
Paclitaxel (PTX) is a commonly used drug to treat diverse cancer types. However, its treatment can generate resistance and the mechanisms of PTX-resistance in lung cancers are still unclear. We demonstrated that non-small cell lung cancers (NSCLCs) survive PTX treatment. Compared with the progenitor NSCLC A549 cells, the PTX-resistant A549 cells (A549/PTX) displayed enhanced sphere-formation ability. The proportion of the cancer stem cell marker, aldehyde dehydrogenase-positive cells, and epithelial–mesenchymal transition signaling protein levels were also elevated in A549/PTX. Importantly, the levels of oncoproteins phosphoinositide-3 kinase/Akt, mucin 1 cytoplasmic domain (MUC1-C) and β-catenin were also significantly elevated in A549/PTX. Furthermore, nuclear translocation of MUC1-C and β-catenin increased in A549/PTX. The c-SRC protein, an activator of MUC1-C, was also overexpressed in A549/PTX. These observations led to the hypothesis that enhanced expression of MUC1-C is associated with stemness and PTX resistance in NSCLCs. To test this, we knocked down or overexpressed MUC1-C in A549/PTX and found that inhibition of MUC1-C expression coupled with PTX treatment was sufficient to reduce the sphere-forming ability and survival of A549/PTX. In summary, our in vitro and in vivo studies have revealed a potential mechanism of MUC1-C-mediated PTX resistance and provided insights into a novel therapeutic measure for lung cancers.
Highlights
Lung cancer has high incidence and mortality rates[1] and is classified into two major histological types: small cell lung carcinoma and non-small cell lung carcinoma (NSCLC)
PTX resistance is mediated via a regulator of epithelial–mesenchymal transition (EMT) in A549 cells Previous studies have reported that drug-resistant cancer cells have active stem-like features and certain characteristics.[14]
The A549 utility of the assay in evaluating self-renewal and differentiation at NSCLC cell line expressed low levels of mucin 1 cytoplasmic domain (MUC1-C) compared with the single-cell level in vitro.[27]
Summary
Lung cancer has high incidence and mortality rates[1] and is classified into two major histological types: small cell lung carcinoma and non-small cell lung carcinoma (NSCLC). Conventional chemotherapeutic drugs diffuse into normal cells in an aggressive and nonspecific manner resulting in unwanted organ-related toxicity.[4] Paclitaxel (PTX) is one of the important first-line chemotherapeutic agents used against a wide range of malignancies.[5] It has proven efficacy against multiple cancers, including breast, ovarian, prostate and NSCLC and small cell lung cancer.[6] Taxanes such as PTX and docetaxel are highly effective for the treatment of cancer and several other diseases. These drugs target the microtubule cytoskeleton that is important in cell division. Taxane-type resistance arises when microtubule mutations have occurred, and the development of taxane resistance limits the efficacy of this types of drugs, such as PTX.[7,8,9]
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