Abstract
Besides its therapeutic effects, chemotherapeutic agents also enhance the malignancy of treated cancers in clinical situations. Recently, epithelial-mesenchymal transition (EMT) has attracted attention in studies of tumor progression. We aimed to test whether transient Adriamycin treatment induces EMT and apoptosis simultaneously in cancer cells, clarify why the same type of cells responds differentially (i.e., apoptosis, EMT) to Adriamycin treatment, and elucidate the role of Twist1, the master regulator of EMT, in this process. In unsynchronized MCF7 cells or cells synchronized at different phases, apoptosis, EMT, and concurrent events [multidrug resistance (MDR) and tumor invasion] after Adriamycin or/and Twist1 small interfering RNA treatment were examined in vitro and in vivo. The Adriamycin-induced Twist1 expression and the interaction of Twist1 with p53-Mdm2 were examined by immunoblotting and immunoprecipitation, respectively. We showed in vitro that Adriamycin induced EMT and apoptosis simultaneously in a cell cycle-dependent manner. Only the cells undergoing EMT displayed enhanced invasion and MDR. Twist1 depletion completely blocked the mesenchymal transformation, partially reversed MDR, and greatly abolished invasion induced by Adriamycin. Also, we confirmed in vivo that Twist1 RNA interference improved the efficacy of Adriamycin for breast cancers. Further, Twist1 reduction in Adriamycin-treated cells promoted p53-dependent p21 induction and disrupted the association of p53 with Mdm2. Our studies show the diverse responses to Adriamycin treatment in cells at different phases, suggest an unrecognized role of EMT in regulating MDR and invasion, and show the efficacy of Twist1 RNA interference in Adriamycin-based chemotherapies for breast cancer.
Highlights
IntroductionChemotherapeutic agents enhance the malignancy of treated cancers in clinical situations
Besides its therapeutic effects, chemotherapeutic agents enhance the malignancy of treated cancers in clinical situations
Our data revealed that Twist1is a multipotent molecule involved in the regulation of epithelialmesenchymal transition, apoptosis, multidrug resistance, and tumor metastasis; the concomitant use of Twist1small interfering RNA during chemotherapy should be a potential therapeutic approach to improve the efficacy of Adriamycin for breast cancer
Summary
Chemotherapeutic agents enhance the malignancy of treated cancers in clinical situations. Conclusions: Our studies show the diverse responses to Adriamycin treatment in cells at different phases, suggest an unrecognized role of EMT in regulating MDR and invasion, and show the efficacy of Twist1RNA interference in Adriamycin-based chemotherapies for breast cancer. Our study well explains the opposite effects of chemotherapy and provides the possible strategies in clinical oncotherapy as follows: On one hand, because breast cancer cells at different phases respond differentially to Adriamycin treatment, it is essential to determine the cell cycle before the administration of chemotherapeutic agents in clinical situations. Our data revealed that Twist1is a multipotent molecule involved in the regulation of epithelialmesenchymal transition, apoptosis, multidrug resistance, and tumor metastasis; the concomitant use of Twist1small interfering RNA during chemotherapy should be a potential therapeutic approach to improve the efficacy of Adriamycin for breast cancer
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