BAG3‐dependent expression of Mcl‐1 confers resistance of mutant <i>KRAS</i> colon cancer cells to the HSP90 inhibitor AUY922

Wang, Chun Yan; Guo, Su; Croft, Amanda; Yan, Xu Guang; Jin, Lei; Zhang, Xu Dong; Jiang, Chen Chen

doi:10.1002/mc.22755

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…The antiapoptotic protein Mcl-1 is located in the mitochondria and often leads to drug resistance in solid tumors because of its high expression. In mutant KRAS colon cancer cells, the high expression of Mcl-1 is stabilized by the Bcl-2-associated athanogene domain 3 (BAG3), which is upregulated by the heat shock factor 1 (HSF1) and downstream of XBP1, and HSF1 can cause resistance to the HSP90 inhibitor AUY922 (Wang et al, 2018; Figure 1).…”

Section: Antiapoptotic Genes Of the Bcl-2 Familymentioning

confidence: 99%

“…The targeted regulation of ERS-related regulatory factors and effectors and combining them with antitumor drugs are useful in improving drug sensitivity. For example, since the HSF1/BAG3/Mcl-1 axis can protect mutated KRAS colon cancer cells from AUY922-induced apoptosis, it is of potential significance to target this axis for improving the efficacy of AUY922 in colon cancer treatment (Wang et al, 2018). NF-κB inhibition enhances imiquimod-induced apoptosis of the melanoma cells and reverses chemotherapy resistance (El-Khattouti et al, 2016).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

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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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Section: Antiapoptotic Genes Of the Bcl-2 Familymentioning

confidence: 99%

Section: Concluding Remarks and Future Perspectivesmentioning

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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“…Due to the remarkably increased tendency of chaperone induced by ER-stress response, many studies have targeted chaperone as a therapeutic target. GRP94, as a common chaperone, HSP90 inhibitor geldanamycin and AUY922 causes cell death ( Marcu et al, 2002 ; Wang et al, 2018 ). Strikingly, some of the agents are nonspecific inhibitors with lower toxicity displaying power and selectivity for GRP94 ( Duerfeldt et al, 2012 ).…”

Section: Treatment Of Intestinal Diseases Targeting Er Stressmentioning

confidence: 99%

Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases

Gao

Hua

et al. 2022

Front. Mol. Biosci.

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The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.

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“…BAG3 has been shown to play a role in the regulation of eIF2a phosphorylation and promote macroautophagy, HDAC6 function, and a transcriptional regulatory in its own right and with heat shock factor 1 (HSF1) [42][43][44][45][46]. The IRE1 ER stress pathway has been proposed to regulate the transcription of BAG3 in part by the regulation of HSF1 [46,47]. Over-expression of GRP78 prevents both the phosphorylation of eIF2a and also activation of the IRE1 ER stress pathway and our data demonstrated that expression of GRP78 almost abolished the drug-induced expression of BAG3.…”

Section: Discussionmentioning

confidence: 99%

AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Dent

Booth

Roberts

et al. 2022

Preprint

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Background We defined the mechanisms by which the chaperone ATPase inhibitor AR12 and the multi-kinase inhibitor neratinib interacted to reduce expression of Tau and amyloid-precursor protein (APP) in microglia and neuronal cells. Methods In vitro cell culture; in-cell immunostaining using a Hermes wide-field microscope with densitometric imaging software; transfection of siRNA and plasmids; assessments of autophagy using a plasmid to express LC3-GFP-RFP. Results AR12 and neratinib interacted to increase the phosphorylation of eIF2A S51 and the expression of BAG3, Beclin1 and ATG5, and in parallel, enhanced autophagosome formation and autophagic flux. Knock down of BAG3, Beclin1 or ATG5 abolished autophagosome formation and significantly reduced degradation of p62, LAMP2, Tau, APP, and GRP78 (total and plasma membrane). Knock down of Rubicon, a key component of LC3-associated phagocytosis (LAP), significantly reduced autophagosome formation but not autophagic flux and prevented degradation of Tau, APP, and cell surface GRP78, but not ER-localized GRP78. Knock down of Beclin1, ATG5 or Rubicon or over-expression of GRP78 prevented the significant increase in eIF2A phosphorylation. Knock down of eIF2A prevented the increase in BAG3 expression and significantly reduced autophagosome formation, autophagic flux, and it prevented Tau and APP degradation. Conclusions We conclude that AR12 has the potential to reduce Tau and APP levels in neurons and microglia via the actions of LAP, endoplasmic reticulum stress signaling and macroautophagy. We hypothesize that the initial inactivation of GRP78 catalytic function by AR12 facilitates an initial increase in eIF2A phosphorylation which in turn is essential for greater levels of eIF2A phosphorylation, greater levels of BAG3 and macroautophagy and eventually leading to significant amounts of APP/Tau degradation.

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BAG3‐dependent expression of Mcl‐1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

Cited by 12 publications

References 45 publications

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

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

Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases

AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

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