Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity
Autor: | Daniel Fishman, Keren Merenbakh-Lamin, Israel Sekler, Riva Shmulevich, Ido Wolf, Tami Rubinek, Tsipi Ben Kasus Nissim |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research AMPK Mitochondrion Biology urologic and male genital diseases female genital diseases and pregnancy complications Cell biology Citric acid cycle 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Cancer cell Genetics Phosphorylation Glycolysis Molecular Biology Klotho PI3K/AKT/mTOR pathway |
Zdroj: | Oncogene. 39:4636-4649 |
ISSN: | 1476-5594 0950-9232 |
Popis: | Klotho is a transmembrane protein, which can be shed and act as a circulating hormone and is involved in regulating cellular calcium levels and inhibition of the PI3K/AKT pathway. As a longevity hormone, it protects normal cells from oxidative stress, and as a tumor suppressor it inhibits growth of cancer cells. Mechanisms governing these differential activities have not been addressed. Altered cellular metabolism is a hallmark of cancer and dysregulation of mitochondrial activity is a hallmark of aging. We hypothesized that klotho exerts its differential effects through regulation of these two hallmarks. Treatment with klotho inhibited glycolysis, reduced mitochondrial activity and membrane potential only in cancer cells. Accordingly, global metabolic screen revealed that klotho altered pivotal metabolic pathways, amongst them glycolysis and tricarboxylic acid cycle in breast cancer cells. Alteration of metabolic activity and increased AMP/ATP ratio lead to LKB1-dependent AMPK activation. Indeed, klotho induced AMPK phosphorylation; furthermore, inhibition of LKB1 partially abolished klotho’s tumor suppressor activity. By diminishing deltapsi (Δψ) klotho also inhibited mitochondria Ca2+ shuttling thereby impairing mitochondria communication with SOCE leading to reduced Ca2+ influx by SOCE channels. The reduced SOCE was followed by ER Ca2+ depletion and stress. These data delineate mechanisms mediating the differential effects of klotho toward cancer versus normal cells, and indicate klotho as a potent regulator of metabolic activity. |
Databáze: | OpenAIRE |
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