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Serum deprivation initiates adaptation and survival to oxidative stress in prostate cancer cells.

ABSTRACT: Inadequate nutrient intake leads to oxidative stress disrupting homeostasis, activating signaling, and altering metabolism. Oxidative stress serves as a hallmark in developing prostate lesions, and an aggressive cancer phenotype activating mechanisms allowing cancer cells to adapt and survive. It is unclear how adaptation and survival are facilitated; however, literature across several organisms demonstrates that a reversible cellular growth arrest and the transcription factor, nuclear factor-kappaB (NF-?B), contribute to cancer cell survival and therapeutic resistance under oxidative stress. We examined adaptability and survival to oxidative stress following nutrient deprivation in three prostate cancer models displaying varying degrees of tumorigenicity. We observed that reducing serum (starved) induced reactive oxygen species which provided an early oxidative stress environment and allowed cells to confer adaptability to increased oxidative stress (H2O2). Measurement of cell viability demonstrated a low death profile in stressed cells (starved?+?H2O2), while cell proliferation was stagnant. Quantitative measurement of apoptosis showed no significant cell death in stressed cells suggesting an adaptive mechanism to tolerate oxidative stress. Stressed cells also presented a quiescent phenotype, correlating with NF-?B nuclear translocation, suggesting a mechanism of tolerance. Our data suggests that nutrient deprivation primes prostate cancer cells for adaptability to oxidative stress and/or a general survival mechanism to anti-tumorigenic agents.

SUBMITTER: White EZ

PROVIDER: S-EPMC7385110 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Serum deprivation initiates adaptation and survival to oxidative stress in prostate cancer cells.

White ElShaddai Z EZ Pennant Nakea M NM Carter Jada R JR Hawsawi Ohuod O Odero-Marah Valerie V Hinton Cimona V CV

Scientific reports 20200727 1

Inadequate nutrient intake leads to oxidative stress disrupting homeostasis, activating signaling, and altering metabolism. Oxidative stress serves as a hallmark in developing prostate lesions, and an aggressive cancer phenotype activating mechanisms allowing cancer cells to adapt and survive. It is unclear how adaptation and survival are facilitated; however, literature across several organisms demonstrates that a reversible cellular growth arrest and the transcription factor, nuclear factor-ka ...[more]

PMID: 32719369

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Project description:IntroductionHigh folate has an association with advanced prostate cancer and levels of testosterone. Herein, we perform a translational study to investigate the inverse response of serum folate in prostate cancer patients initiating androgen deprivation therapy (ADT) and a mirrored animal model.MethodsA retrospective study was performed using the South Texas Veterans Healthcare System to identify patients with prostate cancer on ADT. We documented testosterone and folate levels before and after ADT initiation (defined by a reduction in testosterone by 50 ng/ml) as compared to those already on ADT (maintenance). Our primary outcome was overall mortality with secondary outcome of prostate cancer-specific mortality. In parallel, we tested castration of C57BL/6J mice on folate-defined diet to determine if folate levels change with response to androgen deprivation. Students' t test on continuous variables and Chi-squared test on dichotomous variables was performed along with Kaplan-Meier for time to event analysis.ResultsWe identified 56 men with prostate cancer undergoing androgen deprivation in which folate levels had been determined. 15 out of 16 (94%) men initiating ADT had increases in their folate, which is substantially more than 67% in maintenance group (P = 0.04). We identified more rapid time to death from prostate cancer if folate levels increased to levels >200 ng/ml above their baseline (P = 0.03). Mice models demonstrated a significant rise in serum red blood cell folate after mice were castrated (P = 0.03) by an average of 1.5x over pre-castrated baseline level. By contrast, sham-castrated mice showed no increase in serum folate levels over baseline.ConclusionOur study suggests that men with substantial rises in folate after initiating ADT may be associated with worse prostate cancer-specific and overall survival. Our translational experiments in mice confirmed correlation between rising in folate levels post-castration. Given this study, further investigation is warranted on the role of dietary folate consumption during initiation of ADT and progression to castrate-resistant prostate cancer.

Project description:BackgroundTumourigenic cells modify metabolic pathways in order to facilitate increased proliferation and cell survival resulting in glucose- and glutamine addiction. Previous research indicated that glutamine deprivation resulted in potential differential activity targeting tumourigenic cells more prominently. This is ascribed to tumourigenic cells utilising increased glutamine quantities for enhanced glycolysis- and glutaminolysis. In this study, the effects exerted by glutamine deprivation on reactive oxygen species (ROS) production, mitochondrial membrane potential, cell proliferation and cell death in breast tumourigenic cell lines (MCF-7, MDA-MB-231, BT-20) and a non-tumourigenic breast cell line (MCF-10A) were investigated.ResultsSpectrophotometry demonstrated that glutamine deprivation resulted in decreased cell growth in a time-dependent manner. MCF-7 cell growth was decreased to 61% after 96 h of glutamine deprivation; MDA-MB-231 cell growth was decreased to 78% cell growth after 96 h of glutamine deprivation, MCF-10A cell growth was decreased 89% after 96 h of glutamine deprivation and BT-20 cell growth decreased to 86% after 24 h of glutamine deprivation and remained unchanged until 96 h of glutamine deprivation. Glutamine deprivation resulted in oxidative stress where superoxide levels were significantly elevated after 96 h in the MCF-7- and MDA-MB-231 cell lines. Time-dependent production of hydrogen peroxide was accompanied by aberrant mitochondrial membrane potential. The effects of ROS and mitochondrial membrane potential were more prominently observed in the MCF-7 cell line when compared to the MDA-MB-231-, MCF-10A- and BT-20 cell lines. Cell cycle progression revealed that glutamine deprivation resulted in a significant increase in the S-phase after 72 h of glutamine deprivation in the MCF-7 cell line. Apoptosis induction resulted in a decrease in viable cells in all cell lines following glutamine deprivation. In the MCF-7 cells, 87.61% of viable cells were present after 24 h of glutamine deprivation.ConclusionThis study demonstrates that glutamine deprivation resulted in decreased cell proliferation, time-dependent- and cell line-dependent ROS generation, aberrant mitochondrial membrane potential and disrupted cell cycle progression. In addition, the estrogen receptor positive MCF-7 cell line was more prominently affected. This study contributes to knowledge regarding the sensitivity of breast cancer cells and non-tumorigenic cells to glutamine deprivation.

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Serum deprivation initiates adaptation and survival to oxidative stress in prostate cancer cells.

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Serum deprivation initiates adaptation and survival to oxidative stress in prostate cancer cells.

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