Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised

Abstract

AMPK, AMP-activated protein Kinase; AKT, AK strain Transforming serine/threonine kinase; ASNS, asparagine synthetase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, Immunoglobulin Binding Protein; CHOP, C/EBP homologous protein; CQ, chloroquine; DTT, 1,4-Dithiothreitol; EBSS, Earle's balanced salt solution; eIF2α, eukaryotic initiation factor 2 alpha; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum associated degradation; FBS, fetal bovine serum; GCN2, general control non-derepressible 2 factor; GFP, green fluorescent protein; HER2, epidermal growth factor receptor 2; HIF1α, Hypoxia Inducible Factor 1 Subunit Alpha; HRI, heme-regulated inhibitor kinase; Hsp70, heat shock protein 70; IRE1, inositol-required enzyme 1; ISR, integrated stress response; MAL3-101, phenylmethyl 4-[1,1'-biphenyl]-4-yl-1-[6-[[2-(butylamino)-1-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]hexylamino]-6-oxohexyl]-1,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylate; mTOR, mechanistic Target Of Rapamycin; PBS, phosphate buffered saline; PERK, PKR-like endoplasmic reticulum resident kinase; PI, propidium iodide; PKR, Protein Kinase RNA-activated; RFP, red fluorescent protein; RPPA, Reverse Phase Protein Array; S6K, 70‐kDa ribosomal protein S6 kinase; TNBC, triple negative breast cancer; UPR, unfolded protein response; XbpI, X-box binding protein 1.

The Anticancer Ruthenium Compound BOLD-100 Targets Glycolysis and Generates a Metabolic Vulnerability towards Glucose Deprivation

“…However, unexpectedly, HSP70 levels were markedly reduced by 2-DG treatment in the resistant HCTR cells only. This selective decrease of HSP70 in cells with acquired BOLD-100 resistance indicates a generally disturbed proteostasis [65,80] induced by BOLD-100 selection and, thus, provides another explanation for the observed hypersensitivity of resistant cells towards 2-DG treatment. HSP70, as a central protein fate hub, is known to be implicated in several protein degradation pathways, including, amongst others, micro-, macro-, or chaperone-mediated autophagy [81].…”

Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

“…A chaperone-mediated protein degradation pathway, is upregulated in bortezomib (Bz)-resistant multiple myeloma (MM) cells, accompanied with increased levels of lysosomal associated membrane protein 2A (LAMP2A), the rate-limiting factor of the CMA pathway; the inhibition of CMA sensitizes resistant cells to Bz 162 . Recent studies showed that HSP70 inhibition in resistant breast cancer cells might enhance autophagy and chemoresistance 163 . Autophagy has higher levels in most drug resistant cells, and was highest only in drug resistant cells upon HSP70 inhibition 163 .…”

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy

“…Therefore, tumor progression needs proteostasis adjustment by the upregulation of ATF4 and the modulation of cellular stress responses. Recent investigation suggests that GCN2-mediated autophagy prevents proteotoxicity in breast cancer cells and demonstrates complementary mechanisms to ensure survival [ 150 ]. ATF4 or GCN2 expression abrogation significantly inhibited tumor growth in MEFs [ 60 ].…”