Abstract 5393: Association of heat shock proteins as chaperone for STING: A potential link in a key immune activation mechanism revealed by the novel anti-cancer agent PV-10

Abstract Background Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer. Methods We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis. Results We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions. We experimentally characterized the dual function of two genes, DNAJC9 and HSPA14, in lung cancer cells. We further demonstrated the generalization of this dual direction of associations between HSPs and cancer hallmarks, suggesting the necessity to more carefully evaluate HSPs as therapeutic targets and develop highly specific HSP inhibitors for cancer intervention. Conclusions Our study furnishes a holistic view of functional associations of HSPs with cancer hallmarks to aid the development of HSP inhibitors as well as other drugs in cancer therapy.

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Heat Shock Proteins (HSPs) Based Anti-Cancer Vaccines

Current Molecular Medicine ◽

10.2174/156652412803306684 ◽

2012 ◽

Vol 12 (9) ◽

pp. 1183-1197 ◽

Cited By ~ 34

Author(s):

D.R. Ciocca ◽

N. Cayado-Gutierrez ◽

M. Maccioni ◽

F.D. Cuello-Carrion

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Cancer Vaccines ◽

Anti Cancer ◽

Shock Proteins

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Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

Cells ◽

10.3390/cells9010060 ◽

2019 ◽

Vol 9 (1) ◽

pp. 60 ◽

Cited By ~ 18

Author(s):

Chul Won Yun ◽

Hyung Joo Kim ◽

Ji Ho Lim ◽

Sang Hun Lee

Keyword(s):

Heat Shock ◽

Cancer Therapy ◽

Heat Shock Proteins ◽

Therapeutic Targets ◽

Large Family ◽

Therapy Resistance ◽

Cancer Drug ◽

Cancer Drug Resistance ◽

Anti Cancer ◽

Shock Proteins

Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.

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Heat Shock Proteins and Ovarian Cancer: Important Roles and Therapeutic Opportunities

Cancers ◽

10.3390/cancers11091389 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1389 ◽

Cited By ~ 11

Author(s):

Abdullah Hoter ◽

Hassan Y. Naim

Keyword(s):

Ovarian Cancer ◽

Heat Shock ◽

Heat Shock Proteins ◽

Drug Targets ◽

Survival Rates ◽

Delayed Diagnosis ◽

Body Of Knowledge ◽

Anti Cancer ◽

Cancer Types ◽

Shock Proteins

Ovarian cancer is a serious cause of death in gynecological oncology. Delayed diagnosis and poor survival rates associated with late stages of the disease are major obstacles against treatment efforts. Heat shock proteins (HSPs) are stress responsive molecules known to be crucial in many cancer types including ovarian cancer. Clusterin (CLU), a unique chaperone protein with analogous oncogenic criteria to HSPs, has also been proven to confer resistance to anti-cancer drugs. Indeed, these chaperone molecules have been implicated in diagnosis, prognosis, metastasis and aggressiveness of various cancers. However, relative to other cancers, there is limited body of knowledge about the molecular roles of these chaperones in ovarian cancer. In the current review, we shed light on the diverse roles of HSPs as well as related chaperone proteins like CLU in the pathogenesis of ovarian cancer and elucidate their potential as effective drug targets.

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