Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

Abstract

We studied human cancer cell models in which we detected constitutive activation of ERK. A fraction of active ERK was found to be located in mitochondria in RWPE-2 cells, obtained by v-Ki-Ras transformation of the epithelial prostate RWPE-1 cell line; in metastatic prostate cancer DU145 cells; and in osteosarcoma SAOS-2 cells. All these tumor cells displayed marked resistance to death caused by apoptotic stimuli like arachidonic acid and the BH3 mimetic EM20-25, which cause cell death through the mitochondrial permeability transition pore (PTP). PTP desensitization and the ensuing resistance to cell death induced by arachidonic acid or EM20-25 could be ablated by inhibiting ERK with the drug PD98059 or with a selective ERK activation inhibitor peptide. ERK inhibition enhanced glycogen synthase kinase-3 (GSK-3)-dependent phosphorylation of the pore regulator cyclophilin D, whereas GSK-3 inhibition protected from PTP opening. Neither active ERK in mitochondria nor pore desensitization was observed in nontransformed RWPE-1 cells. Thus, in tumor cells mitochondrial ERK activation desensitizes the PTP through a signaling axis that involves GSK-3 and cyclophilin D, a finding that provides a mechanistic basis for increased resistance to apoptosis of neoplastic cells.

High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells

“…Further, high glucoseinduced phosphorylation of p38 in human endothelial cells leads to cell death (Nakagami et al 2001). ERK1/2 activity is associated with invasive and metastatic properties (Whyte et al 2009); its activation results in desensitization of pore opening and increased resistance to death stimuli, providing advantage to tumor cells (Rasola et al 2010). Our results show that cellular stress under a high-glucose condition in MCF-7 cells results in activation of p38 and de-phosphorylation of ERK, thereby leading to cell death.…”

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

“…It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells. 10,11 GSK3β also has other proposed mechanisms of action, including a poorly characterized role in calcium (Ca 2+ ) homeostasis regulation 12 and protein-protein interactions, 9 as well as functions in different subcellular fractions such as the nucleus, cytosol and mitochondria. 13 Reperfusion is the most powerful intervention to salvage ischemic myocardium.…”

Asterosaponins from the Starfish <i>Astropecten monacanthus</i> Suppress Growth and Induce Apoptosis in HL-60, PC-3, and SNU-C5 Human Cancer Cell Lines

“…22,23) To establish the MAPK and PI3K/AKT mechanism of apoptosis induced by the MeOH extract and compound 5, we examined the expression of ERK 1/2 MAPK and AKT in HL-60, PC-3, and SNU-C5 cells. Treatment with either the MeOH extract or compound 5 significantly decreased phospho-ERK1/2 and phospho-AKT levels (Figs.…”