http://www.karger.co...FullText/447844
http://www.karger.co...icle/Pdf/447844
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Abstract
Background/Aims:
Resveratrol and its derivate piceatannol are known to induce cancer cell-
specific cell death. While multiple mechanisms of actions have been described including the
inhibition of ATP synthase, changes in mitochondrial membrane potential and ROS levels,
the exact mechanisms of cancer specificity of these polyphenols remain unclear. This paper
is designed to reveal the molecular basis of the cancer-specific initiation of cell death by
resveratrol and piceatannol.
Methods:
The two cancer cell lines EA.hy926 and HeLa, and
somatic short-term cultured HUVEC were used. Cell viability and caspase 3/7 activity were
tested. Mitochondrial, cytosolic and endoplasmic reticulum Ca2+ as well as cytosolic and
mitochondrial ATP levels were measured using single cell fluorescence microscopy and
respective genetically-encoded sensors. Mitochondria-ER junctions were analyzed applying
super-resolution SIM and ImageJ-based image analysis.
Results:
Resveratrol and piceatannol
selectively trigger death in cancer but not somatic cells. Hence, these polyphenols strongly
enhanced mitochondrial Ca2+ uptake in cancer exclusively. Resveratrol and piceatannol
predominantly affect mitochondrial but not cytosolic ATP content that yields in a reduced
SERCA activity. Decreased SERCA activity and the strongly enriched tethering of the ER and
mitochondria in cancer cells result in an enhanced MCU/Letm1-dependent mitochondrial
Ca2+ uptake upon intracellular Ca2+ release exclusively in cancer cells. Accordingly, resveratrol/
piceatannol-induced cancer cell death could be prevented by siRNA-mediated knock-down
of MCU and Letm1.
Conclusions:
Because their greatly enriched ER-mitochondria tethering,
cancer cells are highly susceptible for resveratrol/piceatannol-induced reduction of SERCA
activity to yield mitochondrial Ca2+ overload and subsequent cancer cell death
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