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2016 ; 39
(4
): 1404-20
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Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca2+
Coupling Between the Greatly Tethered Endoplasmic Reticulum and Mitochondria
#MMPMID27606689
Madreiter-Sokolowski CT
; Gottschalk B
; Parichatikanond W
; Eroglu E
; Klec C
; Waldeck-Weiermair M
; Malli R
; Graier WF
Cell Physiol Biochem
2016[]; 39
(4
): 1404-20
PMID27606689
show ga
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.