Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised
- University of Pittsburgh, United States
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women Research Institute, United States
- Institute for Precision Medicine, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and source files.
Article and author information
Author details
Funding
European Molecular Biology Laboratory (post-doctoral fellowship (ALTF 823-2016))
- Sara Sannino
National Institutes of Health (F30CA250167)
- Megan E Yates
National Institutes of Health (GM131732)
- Jeffrey L Brodsky
National Institutes of Health (DK79307)
- Jeffrey L Brodsky
National Institutes of Health (P30CA047904)
- Jeffrey L Brodsky
Howard Hughes Medical Institute (Howard Hughes Medical Institute Collaborative Innovation award)
- Jeffrey L Brodsky
University of Pittsburgh (Translational and Precision Pharmacology programs (pilot grant))
- Jeffrey L Brodsky
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Sannino et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised
eLife 10:e64977.
https://doi.org/10.7554/eLife.64977
Further reading
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- Cancer Biology
- Cell Biology
The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.
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- Cell Biology
- Medicine
Background:
It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.
Methods:
Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.
Results:
PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.
Conclusions:
This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Funding:
This study was supported by the National Natural Science Foundation of China (82172474).
