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Cisplatin influences acquisition of resistance to molecular-targeted agents through epithelial-mesenchymal transition-like changes.

ABSTRACT: Chemotherapy with platinum agents is the standard of care for non-small-cell lung cancer (NSCLC); however, novel molecular-targeted agents like gefitinib have been approved for advanced NSCLCs, including recurrent cases previously treated with platinum-based chemotherapy. Although these agents show antitumor activity through distinct mechanisms and elicit positive initial responses, tumors invariably develop resistance. Recent studies have revealed mechanisms by which both types of agents induce acquired resistance. However, little is known about whether first-line treatment with either type of agent affects cancer cell susceptibility and development of resistance against subsequent treatment with the other. Using in vitro drug-resistant NSCLC cell models, we provide evidence that acquired cisplatin resistance may reduce the sensitivity of cancer cells to subsequent treatment with a molecular-targeted agent. In addition, first-line cisplatin treatment influenced the mechanism by which cancer cells developed resistance to subsequent treatment with a molecular-targeted agent. The influence of cisplatin on acquisition of resistance to a molecular-targeted agent was associated with epithelial-mesenchymal transition (EMT)-like alterations such as increased expression of mesenchymal markers, morphological change, and AXL tyrosine kinase-mediated increased cell motility. Our findings indicate that the influence of platinum-based chemotherapy on molecular-targeted therapies and the involvement of EMT and EMT-related effectors should be considered when developing therapeutic strategies using antitumor agents, especially in the context of sequential therapy.

SUBMITTER: Kurokawa M

PROVIDER: S-EPMC7657214 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Cisplatin influences acquisition of resistance to molecular-targeted agents through epithelial-mesenchymal transition-like changes.

Kurokawa Maki M Ise Nobuyuki N Omi Kazuya K Goishi Katsutoshi K Higashiyama Shigeki S

Cancer science 20130515 7

Chemotherapy with platinum agents is the standard of care for non-small-cell lung cancer (NSCLC); however, novel molecular-targeted agents like gefitinib have been approved for advanced NSCLCs, including recurrent cases previously treated with platinum-based chemotherapy. Although these agents show antitumor activity through distinct mechanisms and elicit positive initial responses, tumors invariably develop resistance. Recent studies have revealed mechanisms by which both types of agents induce ...[more]

PMID: 23566288

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Project description:Simple Summary Chemotherapeutic agents including cisplatin promote tumor metastasis while inhibiting tumor growth, which still represents a major obstacle for some patients in clinical practices. This study demonstrated that cisplatin induced epithelial-mesenchymal transition and tumor metastasis in lung adenocarcinoma. Further bioinformatic analysis showed that DCBLD2 may play a key role in metastasis after platinum chemotherapy. In terms of mechanism, DCBLD2 stabilized β-catenin through phosphorylation and inactivation of GSK3β, leading to the disintegration of the destruction complex of β-catenin. The accumulated β-catenin transported to the nucleus and promoted the expression of metastasis-related genes. In addition, cisplatin markedly enhanced DCBLD2 (Discoidin, CUB and LCCL domain containing 2) expression via ERK/AP-1 axis. Importantly, DCBLD2-specific siRNAs encapsulated by nanoparticles strikingly inhibited cisplatin-induced metastasis in tumor-bearing mice. Taken together, DCBLD2 mediates cisplatin-induced metastasis and DCBLD2 inhibition is a promising treatment option for preventing chemotherapy-induced metastasis. Abstract Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor metastasis while inhibiting tumor growth, which is a critical issue for certain patients in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 (Discoidin, CUB and LCCL domain containing 2) is a key gene that mediates cisplatin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin enhanced DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently inhibit cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cisplatin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.

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Cisplatin influences acquisition of resistance to molecular-targeted agents through epithelial-mesenchymal transition-like changes.

Publications

Cisplatin influences acquisition of resistance to molecular-targeted agents through epithelial-mesenchymal transition-like changes.

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