Proteotoxicity is not the reason for the dependence of cancer cells on the major chaperone Hsp70

Colvin, Teresa; Gabai, Vladimir L.; Sherman, Michael Y.

doi:10.4161/cc.29296

Cited by 6 publications

(13 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The concept of the requirement for Hsp70 in cancer cells due to aneuploidy and associated increased demand for chaperones directly predicts that upon knockdown of Hsp70, cancer cells must experience proteotoxic stress. However, as we have recently found, depletion from cultured breast or cervix human cancer cells of the major chaperone Hsp70 did not generate proteotoxic stress 72 . As a measure of proteotoxic stress, several criteria were used in these experiments, including (a) levels of ubiquitinated proteins, (b) activation of Hsf1, (c) activation of Nrf2, a transcription factor that responds to oxidative and proteasome stress, and (d) luciferase refolding in vivo 72 .…”

Section: The Problems With “Non-oncogene Addiction” Hypothesismentioning

confidence: 43%

“…However, as we have recently found, depletion from cultured breast or cervix human cancer cells of the major chaperone Hsp70 did not generate proteotoxic stress 72 . As a measure of proteotoxic stress, several criteria were used in these experiments, including (a) levels of ubiquitinated proteins, (b) activation of Hsf1, (c) activation of Nrf2, a transcription factor that responds to oxidative and proteasome stress, and (d) luciferase refolding in vivo 72 . Similar data were reported with depletion of another major chaperone the member of the small heat shock protein family Hsp27 73 .…”

Section: The Problems With “Non-oncogene Addiction” Hypothesismentioning

confidence: 43%

See 1 more Smart Citation

Hsp70 in cancer: back to the future

2014

View full text Add to dashboard Cite

Mechanistic studies from cell culture and animal models have revealed critical roles for the heat shock protein Hsp70 in cancer initiation and progression. Surprisingly, many effects of Hsp70 on cancer have not been related to its chaperone activity, but rather to its role(s) in regulating cell signaling. A major factor that directs Hsp70 signaling activity appears to be the co-chaperone Bag3. Here, we review these recent breakthroughs, and how these discoveries drive drug development efforts.

show abstract

Section: The Problems With “Non-oncogene Addiction” Hypothesismentioning

confidence: 43%

Section: The Problems With “Non-oncogene Addiction” Hypothesismentioning

confidence: 43%

Hsp70 in cancer: back to the future

2014

View full text Add to dashboard Cite

show abstract

“…HSF1 is overexpressed in many tumors; however, it has not the classic oncogene or tumor‐suppressor role: its action may affect various aspects of tumor‐promoting metabolism (reported schematically in ref. ), so that HSF1 can be counted among those proteins describing the concept of the “non‐oncogenic addiction.” Accordingly, the same thing could be said for HSP70; cancer cells have elevated levels of abnormal proteins, which accumulate because of the tumoral condition and have an imbalance in protein complexes, all features prone to ask for an increase presence of chaperones (i.e., HSP70) and their regulators (i.e., HSF1) . The approach to target the non‐oncogene addiction is progressively rising, thus including HSF1 and HSP70 in appealing non‐oncogenes that could be considered as new therapeutic targets, also in CLL.…”

Section: Introductionmentioning

confidence: 99%

HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia

Frezzato

Raggi

Martini

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.

show abstract

“…This can explain why tumor cells require more chaperones for survival, and the HSP levels increase when cancer progresses [ 24 , 39 , 40 ]. However, a noxious microenvironment cannot explain why tumor cells still need HSP70 in vitro when, as was shown recently, proteotoxic stress either varies markedly between breast cancer cell lines [ 41 ] or is undetectable [ 42 ]. Furthermore, HSP70 is required not only for maintaining the tumor cell viability, but for the malignant transformation itself.…”

Section: Role Of Hsp70 In Oncogenesis and Tumor Progressionmentioning

confidence: 99%

HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy

Kabakov

Gabai²

2021

Cells

View full text Add to dashboard Cite

The high frequency of breast cancer worldwide and the high mortality among women with this malignancy are a serious challenge for modern medicine. A deeper understanding of the mechanisms of carcinogenesis and emergence of metastatic, therapy-resistant breast cancers would help development of novel approaches to better treatment of this disease. The review is dedicated to the role of members of the heat shock protein 70 subfamily (HSP70s or HSPA), mainly inducible HSP70, glucose-regulated protein 78 (GRP78 or HSPA5) and GRP75 (HSPA9 or mortalin), in the development and pathogenesis of breast cancer. Various HSP70-mediated cellular mechanisms and pathways which contribute to the oncogenic transformation of mammary gland epithelium are reviewed, as well as their role in the development of human breast carcinomas with invasive, metastatic traits along with the resistance to host immunity and conventional therapeutics. Additionally, intracellular and cell surface HSP70s are considered as potential targets for therapy or sensitization of breast cancer. We also discuss a clinical implication of Hsp70s and approaches to targeting breast cancer with gene vectors or nanoparticles downregulating HSP70s, natural or synthetic (small molecule) inhibitors of HSP70s, HSP70-binding antibodies, HSP70-derived peptides, and HSP70-based vaccines.

show abstract

Proteotoxicity is not the reason for the dependence of cancer cells on the major chaperone Hsp70

Cited by 6 publications

References 28 publications

Hsp70 in cancer: back to the future

Hsp70 in cancer: back to the future

HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia

HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy

Contact Info

Product

Resources

About