RNAi targeting STMN alleviates the resistance to taxol and collectively contributes to down regulate the malignancy of NSCLC cells in vitro and in vivo

Autor: Xian Chen, Ting Yu, Dan Long, Xuechi Lin, Ying Liao
Rok vydání: 2017
Předmět:
0301 basic medicine
Programmed cell death
Lung Neoplasms
Paclitaxel
Carcinogenesis
Health
Toxicology and Mutagenesis
Cellular differentiation
Cell
Down-Regulation
Mice
Nude
Stathmin
Apoptosis
Biology
Toxicology
Microtubule polymerization
03 medical and health sciences
Inhibitory Concentration 50
RNA interference
Cell Movement
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
medicine
Gene silencing
Animals
Humans
Autocrine signalling
Extracellular Signal-Regulated MAP Kinases
Tumor Stem Cell Assay
Cell Proliferation
Mice
Inbred BALB C
NF-kappa B
Cell Biology
Xenograft Model Antitumor Assays
Cell biology
Interleukin-10
Enzyme Activation
Autocrine Communication
030104 developmental biology
medicine.anatomical_structure
Ki-67 Antigen
Proto-Oncogene Proteins c-bcl-2
Drug Resistance
Neoplasm
Caspases
Cancer research
biology.protein
RNA Interference
Zdroj: Cell biology and toxicology. 34(1)
ISSN: 1573-6822
Popis: Stathmin (STMN) plays a vital role in maintaining the malignant behavior of cancer through directly regulating microtubule dynamics equilibrium. Taxol, an effective chemotherapeutics mainly acting to promote microtubule polymerization, has been commercially applied in treating solid tumors, which results in serious drug resistance. Our study demonstrated that STMN RNA interference (RNAi) enlarged taxol-induced inhibitions in cellular proliferation, colony formation, and multidimensional spaces of cell immigration and decreased half maximal inhibitory concentration (IC50) of taxol in nonsmall cell lung cancer (NSCLC) NCI-H1299 cells; STMN RNAi and taxol jointly attenuated the expressions of extracellular regulated kinase (ERK), nuclear factor kappa B (NF-κB) and B cell lymphoma-2 (Bcl-2), but up regulated Bax expression and initiated intrinsic cell death pathway by activating caspase-3 and caspase-9, while inhibited interleukin 10 (IL-10) autocrine from cell culture supernatant and xenografted mouse serum, as well as intracellular expressions of IL-10 protein and mRNA in vitro; additionally, neutralizing IL-10 alone would incur cell apoptosis to some degree; the further study confirmed that RNAi targeting STMN promoted the sensitivity of taxol in different NSCLC cells. In vivo animal experiments proved that STMN RNAi and taxol cooperatively inhibited the tumorigenicity of NCI-H1299 cells and histological atypia and Ki-67 proliferative index of xenografted tumors and promoted cell differentiation to a higher grade with well-differentiated indicators of glandular lumen-like structure and proliferative fibroblasts. These findings suggest that silencing STMN alleviates the resistance to taxol and collectively contributes to induce the dysfunction of multiple signals and down regulate the malignancy of tumors; thus, STMN is a promising target in treating refractory tumors.
Databáze: OpenAIRE
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