Oxidative Stress Resistance in Metastatic Prostate Cancer: Renewal by Self-Eating

Abstract

Resistant cancer phenotype is a key obstacle in the successful therapy of prostate cancer. The primary aim of our study was to explore resistance mechanisms in the advanced type of prostate cancer cells (PC-3) and to clarify the role of autophagy in these processes. We performed time-lapse experiment (48 hours) with ROS generating plumbagin by using multimodal holographic microscope. Furthermore, we also performed the flow-cytometric analysis and the qRT-PCR gene expression analysis at 12 selected time points. TEM and confocal microscopy were used to verify the results. We found out that autophagy (namely mitophagy) is an important resistance mechanism. The major ROS producing mitochondria were coated by an autophagic membrane derived from endoplasmic reticulum and degraded. According to our results, increasing ROS resistance may be also accompanied by increased average cell size and polyploidization, which seems to be key resistance mechanism when connected with an escape from senescence. Many different types of cell-cell interactions were recorded including entosis, vesicular transfer, eating of dead or dying cells, and engulfment and cannibalism of living cells. Entosis was disclosed as a possible mechanism of polyploidization and enabled the long-term survival of cancer cells. Significantly reduced cell motility was found after the plumbagin treatment. We also found an extensive induction of pluripotency genes expression (NANOG, SOX2, and POU5F1) at the time-point of 20 hours. We suppose, that overexpression of pluripotency genes in the portion of prostate tumour cell population exposed to ROS leads to higher developmental plasticity and capability to faster respond to changes in the extracellular environment that could ultimately lead to an alteration of cell fate.

Quantitative phase imaging unravels new insight into dynamics of mesenchymal and amoeboid cancer cell invasion

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Marine bisindole alkaloid: A potential apoptotic inducer in human cancer cells

“…Multimodal holographic microscope QPHASE (Tescan, Brno, Czech Republic) permits to observe live and fixed cells without any additional staining. 25 , 26 It is based on a robust inverted transmission microscope platform. The whole system is situated in a microscope incubator and includes multiple imaging modes with fully integrated fluorescence module, simulated DIC (differential interference contrast) and brightfield imaging options.…”

Cancer Stem Cells: «Emergency Service» for Tumors Under Generalized Cellular Stress

“…Известно, что SOX2, OCT4/POU5F1, Nanog, KLF4 и c-Myc -пять основных транскрипционных факторов, формирующих транскрипционный профиль стволовых клеток, и их активация является достаточным событием для репрограммирования обычной соматической клетки в плюри/мультипотентную стволовую клетку [141,142]. Показано, что эти транскрипционные факторы активируются в условиях гипоксии [36,38,39,143], оксидативного стресса [77,[144][145][146][147][148] и в присутствии ксенобиотиков [113,114,149]. Таким образом, можно предположить механизм формирования стволового фенотипа опухолевых клеток, подразумевающий активацию этих ключевых факторов в условиях генерализованного клеточного стресса, которая приводит к повышенной экспрессии специфических мишеней, в число которых, вероятно, попадают и гены, обеспечивающие стволовой фенотип клеток Кребс-2.…”