Cisplatin-Induced Giant Cells Formation Is Involved in Chemoresistance of Melanoma Cells.

Chien-Hui Weng,Mei-Lang Kung,Ming-Hsiu Wu,Chieh-Shan Wu,Ming-Hong Tai,Jian-Ching Wu

doi:10.3390/ijms21217892

Abstract

Melanoma is notoriously resistant to current cancer therapy. However, the chemoresistance mechanism of melanoma remains unclear. The present study unveiled that chemotherapy drug cisplatin induced the formation of giant cells, which exhibited enlargement in cell diameter and nucleus in mice and human melanoma cells. Giant cells were positive with melanoma maker S100 and cancer stem cell markers including ABCB5 and CD133 in vitro and in vivo. Moreover, giant cells retained the mitotic ability with expression of proliferation marker Ki-67 and exhibited multiple drug resistance to doxorubicin and actinomycin D. The mitochondria genesis/activities and cellular ATP level were significantly elevated in giant cells, implicating the demand for energy supply. Application of metabolic blockers such as sodium azide or 2-deoxy glucose abolished the cisplatin-induced giant cells formation and expression of cancer stemness markers. The present study unveils a novel chemoresistance mechanism of melanoma cells via size alteration and the anti-neoplastic strategy by targeting giant cells.

Highlights

Melanoma, a malignant tumor of melanocytes, is much more dangerous than other skin cancers, because of its aggressive local growth and metastasis [1,2]
Because the mitochondrial activities were elevated in the giant cells, we evaluated the influence of sodium azide, an inhibitor of the mitochondrial electron transport [28], on the cisplatin-induced formation of giant cells and cancer stemness
In addition to the abovementioned morphological changes, our results demonstrated that the cisplatin-induced giant cells are more malignant because of the overexpression of S100, CD133, and ABCB5 in these giant cells

Summary

Introduction

A malignant tumor of melanocytes, is much more dangerous than other skin cancers, because of its aggressive local growth and metastasis [1,2]. Melanoma has a high mortality and is notoriously resistant to all current modalities of cancer therapy [2,3]. The treatment of malignant melanoma has been limited by its broad resistance to chemotherapy. Cisplatin is one of the most potent and frequently used antitumor agents and is clinically effective against a variety of solid tumors, including ovarian carcinoma, adrenocortical carcinoma, and malignant melanoma [5]. The reduction in intracellular drug accumulation plays a major mechanism of acquired resistance to cisplatin in cancer [7,8,9]. The mechanism of tumor resistance to cisplatin is still not completely understood. It is important to elucidate the mechanism(s) for cisplatin resistance to improve its therapeutic index and overcome the resistance of cancer cells to this therapy

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Conclusion