Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer

Shkedi, Arielle; Taylor, Isabelle R.; Echtenkamp, Frank; Ramkumar, Poornima; Alshalalfa, Mohamed; Rivera‐Marquez, Genesis M.; Moses, Michael A.; Shao, Hao; Karnes, R. Jeffrey; Neckers, Len; Feng, Felix Y.; Kampmann, Martin; Gestwicki, Jason E.

doi:10.1016/j.chembiol.2022.01.008

Cited by 8 publications

(5 citation statements)

References 75 publications

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“…Castration‐resistant PC (CRPC) is dependent on HSP60 through moderate mitochondrial spare respiratory capacity. 123 …”

Section: Heat Shock Proteins In Diseasesmentioning

confidence: 99%

“…Castration-resistant PC (CRPC) is dependent on HSP60 through moderate mitochondrial spare respiratory capacity. 123 Glioblastoma multiforme (GBM) is an aggressive and lethal brain tumor in adults. 124 In GBM, mTORC1 signaling is hyperactivated and promotes growth and proliferation, and thus could be a promising therapeutic HSP27 plays an important role in prostate cancer cell motility and metastatic progression HSP27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E…”

Section: The Role Of Heat Shock Proteins In Cancersmentioning

confidence: 99%

“…Increased level of HSP 60 expression is related to poor survival of PC patients. Castration‐resistant PC (CRPC) is dependent on HSP60 through moderate mitochondrial spare respiratory capacity 123 …”

Section: Heat Shock Proteins In Diseasesmentioning

confidence: 99%

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Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

Yang

Zhou

et al. 2022

MedComm

198

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The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention.

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“…Castration‐resistant PC (CRPC) is dependent on HSP60 through moderate mitochondrial spare respiratory capacity. 123 …”

Section: Heat Shock Proteins In Diseasesmentioning

confidence: 99%

Section: The Role Of Heat Shock Proteins In Cancersmentioning

confidence: 99%

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Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

Yang

Zhou

et al. 2022

MedComm

198

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“…Current findings clearly suggest that cancer cells are highly reliant on the UPR mt for growth and progression, and therefore, aggressive and resistant cancers such as PCa possess robust activation of UPR mt [255,256], which could be targeted for developing novel therapies to cure cancer. Recently, we have identified an inhibitor of UPR mt , a promising new anticancer agent for cancer such as PCa.…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer

Inigo

Chandra

2022

J Hematol Oncol

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Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.

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“…In patients with PCa, serum levels of HSP70s were significantly higher than in patients without PCa [ 34 ]. In addition, castration resistant prostate cancer (CRPC) is associated with increased reliance on HSP70s [ 35 ], and GRP78 expression is significantly elevated in metastatic CRPC compared with localized prostate cancer [ 36 ]. Moreover, GRP75 expression correlates with increased risk of high-grade prostate adenocarcinoma [ 37 ].…”

Section: Hsp Familymentioning

confidence: 99%

Heat Shock Protein 70 and 90 Family in Prostate Cancer

Liu

Yan

et al. 2022

Life

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Prostate cancer (PCa) is the second most frequent cancer that affects aging men worldwide. However, its exact pathogenesis has not been fully elucidated. The heat shock protein (HSP) family has cell-protective properties that may promote tumor growth and protect cancer cells from death. On a cellular level, HSP molecules have a strong relationship with multiple important biological processes, such as cell differentiation, epithelial–mesenchymal transition (EMT), and fibrosis. Because of the facilitation of HSP family molecules on tumorigenesis, a number of agents and inhibitors are being developed with potent antitumor effects whose target site is the critical structure of HSP molecules. Among all target molecules, HSP70 family and HSP90 are two groups that have been well studied, and therefore, the development of their inhibitors makes great progress. Only a small number of agents, however, have been clinically tested in recruited patients. As a result, more clinical studies are warranted for the establishment of the relationship between the HSP70 family, alongside the HSP90 molecule, and prostate cancer treatment.

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Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer

Cited by 8 publications

References 75 publications

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities

The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer

Heat Shock Protein 70 and 90 Family in Prostate Cancer

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