Autophagy Plays a Critical Role in Insulin Resistance- Mediated Chemoresistance in Hepatocellular Carcinoma Cells by Regulating the ER Stress

Li, Linjing; Zhou, Liye; Wang, Wei; Liu, Zhuan; Cheng, Yan; Li, Jing; Wei, Hulai

doi:10.7150/jca.27943

Cited by 16 publications

(14 citation statements)

References 42 publications

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“…Moreover, the conversion of LC3BI (the soluble LC3B isoform) into LC3BII was enhanced in resistant cells ( Figure 2D and Figure 2—figure supplement 1E ), as evidenced by the increased LC3BII:LC3BI ratio ( Barth et al, 2010 ; McLeland et al, 2011 ; Zhang et al, 2016 ). The magnitude of this effect is consistent with other studies demonstrating autophagy induction ( Klionsky et al, 2016 ; Li et al, 2018 ; Rouschop et al, 2010 ; Sannino et al, 2018 ).…”

Section: Resultssupporting

confidence: 92%

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

Sannino

Yates

Schurdak

et al. 2021

eLife

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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.

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Section: Resultssupporting

confidence: 92%

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

Sannino

Yates

Schurdak

et al. 2021

eLife

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“…PERK-mediated ATF4 activation can up-regulate autophagy-related genes such as LC3, BECN1, Atg3, Atg12 and Atg16L1. Although ER stress and autophagy work independently, they share many common features, including protecting cells by reducing stress and inducing cell death under extreme conditions 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis

Zheng¹,

Liu²,

Liu³

et al. 2022

J. Cancer

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PERK is one of the transmembrane sensors of unfolded protein response (UPR) triggered by ER stress. In this study, we evaluated the role of PERK in the sensitivity of hepatocellular carcinoma (HCC) cells to high linear energy transfer (LET) carbon ions (CI). We found that CI irradiation could induce ER stress in HCC cells. On the one hand, PERK promoted autophagy via regulating ATF4 expression; on the other hand, PERK regulated p53 expression, and the latter either induced autophagy through up-regulating DRAM, or directly promoting apoptosis through the mitochondrial pathway or facilitating ferroptosis via down-regulating SLC7A11 (the extrinsic pathway), but independent of GPX4 (the intrinsic pathway). These factors jointly determined the sensitivity of HCC cells to high-LET CI radiation. Inhibiting TP53 directly increased cellular radioresistance definitely. Moreover, the death of HepG2 (TP53 wild type) cells induced by high-LET CI irradiation combined with sorafenib treatment might be caused by a mixed-type regulated cell death (RCD) including both apoptosis and ferroptosis, suggesting that apoptosis and ferroptosis are synergetic cell death modes regulated by TP53, which is one of the reasons why the sensitivity of HepG2 cells is higher than that of Hep3B (TP53 null type) and PLC/PRF5 (TP53 mutated type) cells. Therefore, our work might shed light on the potential therapeutic implication of CI radiotherapy combined with PERK targeted clinical drugs to implement personalized and precise treatment of HCCs.

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“…Basic results obtained so far on this topic have suggested ( Avril et al, 2017 ; Bahar et al, 2019 ) that ERS-mediated tumor cell survival is gradually becoming the key factor in solid tumor drug resistance. In the past years, with the increasing application of drugs and the deepening of research in this domain, many basic reports have been published ( Cubillos-Ruiz et al, 2017 ; Jin et al, 2017 ; Li L. et al, 2018 ) on drug resistance mediated by drug-induced ERS, such as intrinsic apoptosis inhibition, protective autophagy, ABC transporters, and extrinsic immunosuppression. However, a systemic report on drug resistance in solid tumor cells has not yet been published.…”

Section: Introductionmentioning

confidence: 99%

The Road of Solid Tumor Survival: From Drug-Induced Endoplasmic Reticulum Stress to Drug Resistance

Cao

Tang

Huang

et al. 2021

Front. Mol. Biosci.

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Endoplasmic reticulum stress (ERS), which refers to a series of adaptive responses to the disruption of endoplasmic reticulum (ER) homeostasis, occurs when cells are treated by drugs or undergo microenvironmental changes that cause the accumulation of unfolded/misfolded proteins. ERS is one of the key responses during the drug treatment of solid tumors. Drugs induce ERS by reactive oxygen species (ROS) accumulation and Ca2+ overload. The unfolded protein response (UPR) is one of ERS. Studies have indicated that the mechanism of ERS-mediated drug resistance is primarily associated with UPR, which has three main sensors (PERK, IRE1α, and ATF6). ERS-mediated drug resistance in solid tumor cells is both intrinsic and extrinsic. Intrinsic ERS in the solid tumor cells, the signal pathway of UPR-mediated drug resistance, includes apoptosis inhibition signal pathway, protective autophagy signal pathway, ABC transporter signal pathway, Wnt/β-Catenin signal pathway, and noncoding RNA. Among them, apoptosis inhibition is one of the major causes of drug resistance. Drugs activate ERS and its downstream antiapoptotic proteins, which leads to drug resistance. Protective autophagy promotes the survival of solid tumor cells by devouring the damaged organelles and other materials and providing new energy for the cells. ERS induces protective autophagy by promoting the expression of autophagy-related genes, such as Beclin-1 and ATG5–ATG12. ABC transporters pump drugs out of the cell, which reduces the drug-induced apoptosis effect and leads to drug resistance. In addition, the Wnt/β-catenin signal pathway is also involved in the drug resistance of solid tumor cells. Furthermore, noncoding RNA regulates the ERS-mediated survival and death of solid tumor cells. Extrinsic ERS in the solid tumor cells, such as ERS in immune cells of the tumor microenvironment (TME), also plays a crucial role in drug resistance by triggering immunosuppression. In immune system cells, ERS in dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) influences the antitumor function of normal T cells, which results in immunosuppression. Meanwhile, ERS in T cells can also cause impaired functioning and apoptosis, leading to immunosuppression. In this review, we highlight the core molecular mechanism of drug-induced ERS involved in drug resistance, thereby providing a new strategy for solid tumor treatment.

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Autophagy Plays a Critical Role in Insulin Resistance- Mediated Chemoresistance in Hepatocellular Carcinoma Cells by Regulating the ER Stress

Cited by 16 publications

References 42 publications

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

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

PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis

The Road of Solid Tumor Survival: From Drug-Induced Endoplasmic Reticulum Stress to Drug Resistance

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