FOXP3 Controls an miR-146/NF-κB Negative Feedback Loop That Inhibits Apoptosis in Breast Cancer Cells

AbstractAdaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can generate majorly two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of TCGA breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multistability and drive phenotypic switching and heterogeneity in a cancer cell population.

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Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells

Journal of Clinical Medicine ◽

10.3390/jcm10030472 ◽

2021 ◽

Vol 10 (3) ◽

pp. 472

Author(s):

Adithya Chedere ◽

Kishore Hari ◽

Saurav Kumar ◽

Annapoorni Rangarajan ◽

Mohit Kumar Jolly

Keyword(s):

Breast Cancer ◽

Phenotypic Plasticity ◽

Cancer Cells ◽

Cell Population ◽

Negative Feedback ◽

Feedback Loop ◽

The Cancer Genome Atlas ◽

Phenotypic Switching ◽

Negative Feedback Loop ◽

Double Negative

Adaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK (AMP-activated protein kinase) and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can significantly generate two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of The Cancer Genome Atlas (TCGA) breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multi-stability and drive phenotypic switching and heterogeneity in a cancer cell population.

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A Repertoire of MicroRNAs Regulates Cancer Cell Starvation by Targeting Phospholipase D in a Feedback Loop That Operates Maximally in Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.00711-15 ◽

2016 ◽

Vol 36 (7) ◽

pp. 1078-1089 ◽

Cited By ~ 12

Author(s):

Kristen Fite ◽

Lobna Elkhadragy ◽

Julian Gomez-Cambronero

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Phospholipase D ◽

Negative Feedback ◽

Breast Cancer Cells ◽

Feedback Loop ◽

Nutrient Starvation ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition

We report a negative feedback loop between the signaling protein phospholipase D (PLD), phosphatidic acid (PA), and a specific set of microRNAs (miRNAs) during nutrient starvation of breast cancer cells. We show that PLD expression is increased in four breast cancer cell lines and that hypoxia, cell overcrowding, and nutrient starvation for 3 to 6 h increase expression even further. However, after prolonged (>12-h) starvation, PLD levels return to basal or lower levels. The mechanism for this is as follows. First, during initial starvation, an elevated PA (the product of PLD enzymatic activity) activates mTOR and S6K, known to inhibit apoptosis, and enhances cell migration especially in post-epithelial-to-mesenchymal transition (post-EMT) cancer cells. Second, continued PA production in later starvation induces expression of PLD-targeting microRNA 203 (miR-203), miR-887, miR-3619-5p, and miR-182, which reduce PLD translation. We provide direct evidence for a feedback loop, whereby PLD induction upon starvation leads to PA, which induces expression of miRNAs, which in turn inhibits PLD2 translation. The physiological relevance for breast cancer cells is that as PA can activate cell invasion, then, due to the negative feedback, it can deprive mTOR and S6K of their natural activator. It can further prevent inhibition of apoptosis and allow cells to survive nutrient deprivation, which normal cells cannot do.

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