Staurosporine Induces the Generation of Polyploid Giant Cancer Cells in Non-Small-Cell Lung Carcinoma A549 Cells

Glassmann, Alexander; Garcia, Carmen Carrillo; Janzen, Viktor; Kraus, Dominik; Veit, Nadine; Winter, Jochen; Probstmeier, Rainer

doi:10.1155/2018/1754085

Cited by 16 publications

(18 citation statements)

References 28 publications

(33 reference statements)

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“…There is a small body of literature specifically related to PGCCs (74 PubMed‐listed entries with query: [PGCCs] vs 3,857,567 with query [cancer]; accessed 10 May 2019; Figure ), but this literature, taken holistically, makes a compelling case for defining them as the essential keystone cancer species and actuators of tumorigenesis, therapeutic resistance, and recurrence in metastatic disease. Keystone species are relatively few in number, but have a significant impact on the health and composition of the ecosystem.…”

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confidence: 99%

Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance

et al. 2019

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Cancer led to the deaths of more than 9 million people worldwide in 2018, and most of these deaths were due to metastatic tumor burden. While in most cases, we still do not know why cancer is lethal, we know that a total tumor burden of 1 kg—equivalent to one trillion cells—is not compatible with life. While localized disease is curable through surgical removal or radiation, once cancer has spread, it is largely incurable. The inability to cure metastatic cancer lies, at least in part, to the fact that cancer is resistant to all known compounds and anticancer drugs. The source of this resistance remains undefined. In fact, the vast majority of metastatic cancers are resistant to all currently available anticancer therapies, including chemotherapy, hormone therapy, immunotherapy, and systemic radiation. Thus, despite decades—even centuries—of research, metastatic cancer remains lethal and incurable. We present historical and contemporary evidence that the key actuators of this process—of tumorigenesis, metastasis, and therapy resistance—are polyploid giant cancer cells.

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confidence: 99%

Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance

et al. 2019

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“…Concerning the cell cycle unbalance and polynucleation in A549 cells, two recent articles commented on these points. The fist paper [17] dealt with the generation of A549-polyploid giant cancer cells (PGCCs) after Staurosporine (STS) treatment. In this context, the authors commented that polynucleated A549 cells might function as blastomere-like stem cells and thus play some roles in tumor heterogeneity, stemness, and resistance.…”

Section: Discussionmentioning

confidence: 99%

Simulated Microgravity Effects on Human Adenocarcinoma Alveolar Epithelial Cells: Characterization of Morphological, Functional, and Epigenetic Parameters

Degan

Cortese

Pulliero

et al. 2021

IJMS

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Background: In space, the reduction or loss of the gravity vector greatly affects the interaction between cells. Since the beginning of the space age, microgravity has been identified as an informative tool in biomedicine, including cancer research. The A549 cell line is a hypotriploid human alveolar basal epithelial cell line widely used as a model for lung adenocarcinoma. Microgravity has been reported to interfere with mitochondrial activity, energy metabolism, cell vitality and proliferation, chemosensitivity, invasion and morphology of cells and organelles in various biological systems. Concerning lung cancer, several studies have reported the ability of microgravity to modulate the carcinogenic and metastatic process. To investigate these processes, A549 cells were exposed to simulated microgravity (µG) for different time points. Methods: We performed cell cycle and proliferation assays, ultrastructural analysis of mitochondria architecture, as well as a global analysis of miRNA modulated under µG conditions. Results: The exposure of A549 cells to microgravity is accompanied by the generation of polynucleated cells, cell cycle imbalance, growth inhibition, and gross morphological abnormalities, the most evident are highly damaged mitochondria. Global miRNA analysis defined a pool of miRNAs associated with µG solicitation mainly involved in cell cycle regulation, apoptosis, and stress response. To our knowledge, this is the first global miRNA analysis of A549 exposed to microgravity reported. Despite these results, it is not possible to draw any conclusion concerning the ability of µG to interfere with the cancerogenic or the metastatic processes in A549 cells. Conclusions: Our results provide evidence that mitochondria are strongly sensitive to µG. We suggest that mitochondria damage might in turn trigger miRNA modulation related to cell cycle imbalance.

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“…One of the potential sources of stem cells is polyploid cells characterized by multinucleation and cell cycle arrest [ 10 , 11 ]. Polyploidy was shown as an adaptation mechanism that allows cancers to tolerate harsh treatment conditions and plays significant role in the drug-resistance of many cancers and cancer cell lines, including NSCLC [ 12 , 13 ]. The polyploid giant cancer cells (PGCCs) could reversibly enter the therapy-induced senescence, allowing them to survive therapy and later re-enter the cell cycle to form daughter cells of typical size and ploidy [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…The polyploid giant cancer cells (PGCCs) could reversibly enter the therapy-induced senescence, allowing them to survive therapy and later re-enter the cell cycle to form daughter cells of typical size and ploidy [ 14 , 15 ]. Therefore, the progeny of metabolically active PGCCs may contribute to cancer recurrence following anticancer treatment [ 12 ]. Moreover, PGCCs have been demonstrated to possess stem cell-like properties, as they express CSCs markers, form spheroids in vitro, and generate tumors in mice [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

Pustovalova

Alhaddad

Blokhina

et al. 2021

IJMS

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Ionizing radiation (IR) is used for patients diagnosed with unresectable non-small cell lung cancer (NSCLC). However, radiotherapy remains largely palliative due to the survival of specific cell subpopulations. In the present study, the sublines of NSCLC cells, A549IR (p53wt) and H1299IR (p53null) survived multifraction X-ray radiation exposure (MFR) at a total dose of 60 Gy were investigated three weeks after the MFR course. We compared radiosensitivity (colony formation), expression of epithelial-mesenchymal transition (EMT) markers, migration activity, autophagy, and HR-dependent DNA double-strand break (DSB) repair in the bulk and entire CD44high/CD166high CSC-like populations of both parental and MFR survived NSCLC cells. We demonstrated that the p53 status affected: the pattern of expression of N-cadherin, E-cadherin, Vimentin, witnessing the appearance of EMT-like phenotype of MFR-surviving sublines; 1D confined migratory behavior (wound healing); the capability of an irradiated cell to continue to divide and form a colony of NSCLC cells before and after MFR; influencing the CD44/CD166 expression level in MFR-surviving NSCLC cells after additional single irradiation. Our data further emphasize the impact of p53 status on the decay of γH2AX foci and the associated efficacy of the DSB repair in NSCLC cells survived after MFR. We revealed that Rad51 protein might play a principal role in MFR-surviving of p53 null NSCLC cells promoting DNA DSB repair by homologous recombination (HR) pathway. The proportion of Rad51 + cells elevated in CD44high/CD166high population in MFR-surviving p53wt and p53null sublines and their parental cells. The p53wt ensures DNA-PK-mediated DSB repair for both parental and MFR-surviving cells irrespectively of a subsequent additional single irradiation. Whereas in the absence of p53, a dose-dependent increase of DNA-PK-mediated non-homologous end joining (NHEJ) occurred as an early post-irradiation response is more intensive in the CSC-like population MFR-surviving H1299IR, compared to their parental H1299 cells. Our study strictly observed a significantly higher content of LC3 + cells in the CD44high/CD166high populations of p53wt MFR-surviving cells, which enriched the CSC-like cells in contrast to their p53null counterparts. The additional 2 Gy and 5 Gy X-ray exposure leads to the dose-dependent increase in the proportion of LC3 + cells in CD44high/CD166high population of both parental p53wt and p53null, but not MFR-surviving NSCLC sublines. Our data indicated that autophagy is not necessarily associated with CSC-like cells’ radiosensitivity, emphasizing that careful assessment of other milestone processes (such as senescence and autophagy-p53-Zeb1 axis) of primary radiation responses may provide new potential targets modulated for therapeutic benefit through radiosensitizing cancer cells while rescuing normal tissue. Our findings also shed light on the intricate crosstalk between autophagy and the p53-related EMT, by which MFR-surviving cells might obtain an invasive phenotype and metastatic potential.

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Staurosporine Induces the Generation of Polyploid Giant Cancer Cells in Non-Small-Cell Lung Carcinoma A549 Cells

Cited by 16 publications

References 28 publications

Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance

Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance

Simulated Microgravity Effects on Human Adenocarcinoma Alveolar Epithelial Cells: Characterization of Morphological, Functional, and Epigenetic Parameters

The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

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