Mammalian Cells Undergo Endoreduplication in Response to Lactic Acidosis

Abstract

Polyploidization, a common event during the evolution of different tumours, has been proposed to confer selective advantages to tumour cells by increasing the occurrence of mutations promoting cancer progression and by conferring chemotherapy resistance. While conditions leading to polyploidy in cancer cells have been described, a general mechanism explaining the incidence of this karyotypic change in tumours is still missing. In this study, we tested whether a widespread tumour microenvironmental condition, low pH, could induce polyploidization in mammalian cells. We found that an acidic microenvironment, in the range of what is commonly observed in tumours, together with the addition of lactic acid, induced polyploidization in transformed and non-transformed human cell lines in vitro. In addition, we provide evidence that polyploidization was mainly driven through the process of endoreduplication, i.e. the complete skipping of mitosis in-between two S-phases. These findings suggest that acidic environments, which characterize solid tumours, are a plausible path leading to polyploidization of cancer cells.

Molecular Cytogenomic Characterization of the Murine Breast Cancer Cell Lines C-127I, EMT6/P and TA3 Hauschka

“…Thus, this is the first evidence that the three cell lines may demonstrate different subtypes and stages of human BC [ 40 ]. However, polyploidization is common in cancer cell lines [ 41 , 42 ], but polyploidization may also be part of malignancy progression and was also observed in connection with drug resistance [ 42 ]. Therefore, the pentaploidy in cell line C-127I may indicate that this cell line may be a suited model for the aggressive stage of BC or the HER2 -enriched subtype which is known as an aggressive subtype and resistant to treatment [ 11 , 34 ].…”

A translational program that suppresses metabolism to shield the genome

“…2). We reasoned that perhaps eIF5A functions as a proliferative brake to safeguard genome integrity during anaerobic acidosis, which significantly increases DNA and chromosomal damage if proliferation is unchecked under such conditions [1][2][3][4] . Indeed, eIF5A-competent cells effectively maintained genomic integrity during acidosis, as determined by DNA-damage measurements using alkaline comet ( Fig.…”

“…he preservation of genomic integrity is essential for organismal survival and evolutionary fitness. This ability is especially critical during physiological stresses that damage DNA [1][2][3][4] . Anaerobic metabolism-induced extracellular acidosis (hereafter referred to as hypoxia or anaerobic acidosis) is one of the most frequently encountered stimuli/stresses in health and diseases, including development, exercise, cancer, and ischemia [5][6][7][8][9] .…”

Cytogenomic characteristics of murine breast cancer cell line JC

“…JC cell line presents a near-tetraploidy karyotype, which is typically observable, especially in human [ 36 ], however, only present in about 50% of murine tumor cell lines [ 1 , 16 , 17 , 19 , 34 , 35 ]. Polyploidy promotes malignant transformation of mammary cells and increases cell resistance to drugs [ 36 ]; still, it is also a known adaptation of cells to cell culture conditions. In case of JC cell line the only available previous cytogenetic characterization dates back to 1989; at that stage the cell line was extremely chromosomally instable with chromosome numbers reported between 28 and 99.…”