Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells.
CD44, a major receptor for hyaluronan (HA), is a member of a class of adhesion molecules of unknown classification involved in cell proliferation, differentiation, migration, angiogenesis, and the presentation of specific cytokines to the corresponding receptors as well as in cell signaling transduction. It has recently been discovered that CD44, a marker of tumor stem cells, is involved in the drug resistance and invasion of multiple types of tumors. The 20 exons in the CD44 gene that are alternatively spliced, give rise to many CD44 isoforms, possibly including tumor-specific sequences. Dozens of CD44 isoforms have been found, to date, and the standard CD44 (CD44s) isoform is the most common. We recently showed that a novel short-tail isoform of CD44 (CD44st) was expressed in multidrug-resistant human breast cancer MCF-7/Adr cells. Moreover, the novel CD44st was able to interact with HA and regulate the expression of matrix metalloproteinase (MMP)-2 and MMP-9, which increased the invasive capability of MCF-7 cells through the Ras/MAPK signaling pathway. In the present study, we verified that MCF-7 cells subjected to drug pressure develop multidrug resistance to doxorubicin, and the expression levels of multidrug resistance protein 1 (MDR1), CD44st and nuclear factor-κB (NF-κB) mRNA and protein were gradually upregulated in a dose‑dependent manner in MCF-7 cells treated with doxorubicin. HA increases the secretion of MMP-2 and MMP-9 in multidrug-resistant MCF-7 cells and affected the invasive ability of MCF-7 cells through the upregulation of CD44st expression, and such an effect was blocked by the NF-κB-specific inhibitor BMS-345541.
Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
Xin Jian
XJ
Fang
Department of Medical Oncology, The Second People's Hospital of Lianyungang (Lianyungang Hospital Affiliated to Bengbu Medical College), Lianyungang, Jiangsu 222000, P.R. China.
Hua
H
Jiang
Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
Ya Qun
YQ
Zhu
Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
Li Yuan
LY
Zhang
Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
Qiu Hong
QH
Fan
Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
Ye
Y
Tian
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D006820:Hyaluronic Acid / Q000008:administration & dosage; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D020033:Protein Isoforms; D004317:Doxorubicin; D006820:Hyaluronic Acid