Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells.

Docetaxel (Doc) plays a crucial role in clinical antineoplastic practice. However, it is continuously documented that tumors frequently develop chemoresistance and relapse, which may be related to polyploid giant cancer cells (PGCCs). The aim of this study was investigate the formation mechanism and biological behavior of PGCCs induced by Doc. Ovarian cancer cells were treated with Doc, and then the effect of Doc on cellular viability was evaluated by MTT assay and microscopic imaging analysis. The biological properties of PGCCs were further evaluated by Hoechst 33342 staining, cell cycle and DNA content assay, DNA damage response (DDR) signaling detection, ß-galactosidase staining, mitochondrial membrane potential detection, and reverse transcription-quantitative polymerase chain reaction. The results indicated that Doc reduced cellular viability; however, many cells were still alive, and were giant and polyploid. Doc increased the proportion of cells stayed in the G2/M phase and reduced the number of cells. In addition, the expression of γ-H2A.X was constantly increased after Doc treatment. PGCCs showed senescence-associated ß-galactosidase activity and an increase in the monomeric form of JC-1. The mRNA level of octamer-binding transcription factor 4 (OCT4) and krüppel-like factor 4 (KLF4) was significantly increased in PGCCs. Taken together, our results suggest that Doc induces G2/M cell cycle arrest, inhibits the proliferation and activates persistent DDR signaling to promote the formation of PGCCs. Importantly, PGCCs exhibit a senescence phenotype and express stem cell markers.

IL-1ß is involved in docetaxel chemoresistance by regulating the formation of polyploid giant cancer cells in non-small cell lung cancer.

Docetaxel (Doc) is a cornerstone of chemotherapy; however, treatment with Doc often and inevitably leads to drug resistance and the formation of polyploid giant cancer cells (PGCCs). In this study, we investigated the effect of Doc on non-small cell lung cancer to explore the role of PGCCs in drug resistance and the molecular mechanisms that regulate this resistance. We found that Doc induced G2/M cell cycle arrest and cell death in A549 and NCI-H1299 cells. However, many cells remained alive and became PGCCs by decreasing the expression of key regulatory proteins related to the cell cycle and proliferation. Notably, the PGCCs showed typical features of senescence, especially upregulation of p21 and p-histone H2A.X expression. Moreover, the mRNA level of IL-1ß in the senescence-associated secretory phenotype was increased significantly with the development of PGCCs. Inhibition of IL-1ß reduced the expression of p-histone H2A.X and promoted polyploidy to enhance the proapoptotic effect of Doc. Taken together, our results suggested that IL-1ß was involved in the formation of PGCCs and regulated the senescence of PGCCs, which contributed to drug resistance to Doc. Therefore, targeting IL-1ß in PGCCs may be a novel approach to overcome drug resistance.

Mesenchymal Stem Cells and their Derived Exosomes Promote Malignant Phenotype of Polyploid Non-Small-Cell Lung Cancer Cells through AMPK Signaling Pathway.

Chemotherapy is an important method for the treatment of non-small-cell lung cancer (NSCLC), but it can lead to side effects and polyploid cancer cells. The polyploid cancer cells can live and generate daughter cancer cells via budding. Mesenchymal stem cells (MSCs) are pluripotent stem cells with repair and regeneration functions and can resist tissue damage caused by tumor therapy. This study is aimed at investigating the effects of MSCs and their derived exosomes on the biological characteristics of polyploid NSCLC cells and the potential mechanisms. We found that MSC conditioned medium (CM), MSCs, and MSC-exosomes had no effect on cell proliferation of the polyploid A549 and H1299 cells. Compared with the control group, MSCs and MSC-exosomes significantly promoted epithelial mesenchymal transformation, cell migration, antiapoptosis, and autophagy in the polyploid A549 and H1299 by activating AMPK signaling pathway, but no significant changes were observed in MSC-CM treatment. These results revealed that MSCs and MSC-exosomes promoted malignant phenotype of polyploid NSCLC cells through the AMPK signaling pathway.

A novel heme oxygenase-1 splice variant, 14kDa HO-1, promotes cell proliferation and increases relative telomere length.

Alternative splicing is a routine phenomenon which greatly increases the diversity of proteins in eukaryotic cells. In humans, most multi-exonic genes are alternatively spliced and their splice variants confer distinct functions. Heme oxygenase-1 (HO-1, 32 kDa) is an inducible stress responsive protein, which possesses multiple functions in many cellular processes. In the current study, we identified a novel alternative splice isoform of 14 kDa HO-1 generated through exclusion of exon 3, and it is highly expressed in immortalized cells. In contrast to nuclear accumulation of the full-length 32 kDa HO-1, the novel 14 kDa HO-1 isoform is retained in the cytoplasm under ultraviolet (UV) irradiation. Interestingly, the 14 kDa HO-1 is shown to promote cell proliferation and an increase in relative telomere lengths in vivo and in vitro. Thus, we are pioneer to report and confirm the presence of a novel splice form of HO-1 and its distinct role in modulating telomere length and tumor growth.