Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.

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The Role of Heat Shock Proteins in Cisplatin Resistance

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180817114952 ◽

2019 ◽

Vol 18 (15) ◽

pp. 2093-2109 ◽

Cited By ~ 6

Author(s):

Zdzisław Krawczyk ◽

Agnieszka Gogler-Pigłowska ◽

Damian R. Sojka ◽

Dorota Scieglinska

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Cancer Cells ◽

Relevant Information ◽

Multiple Observations ◽

Wide Range ◽

Cellular Context ◽

Universal Relationship ◽

Shock Proteins

Background: Cisplatin (CDDP), a small molecule platinum-based compound, is an effective anticancer drug used against a wide range of human neoplasms. Long-term clinical use of CDDP is however limited due to the development of drug resistance and the possible incidence of serious side effects including nephrotoxicity and ototoxicity. The mechanisms underlying resistance of cells to CDDP are complex, and among them, the cytoprotective involvement of proteins referred to as Heat Shock Proteins (HSP) seems potentially important. Methods: We searched various electronic databases including PubMed and selected the reports concerning the contribution of HSPs to CDDP resistance of cancer cells and to minimize the CDDP-induced nephrotoxicity and ototoxicity. Results: This critical review of data collected so far summarizes the results on the major HSPs: HSP27/HSPB1, HSP70/HSPA1, HSP90/HSPC and GRP78/HSPA5, because only these have been the subject of the most intense research in the matter discussed here. We also provide relevant information concerning some other HSPs, namely HSPA9/mortalin, HSPA2, HSP110 and DNAJ. A possible role of HSPs in counteracting CDDP-induced neprho- and ototoxicity is mentioned. Conclusions: This review shows that no universal relationship between the levels of expression of HSPs and sensitivity of cancer cells to CDDP can be confirmed. Multiple observations indicate however that such correlation can rather manifest as a molecular or cellular context-dependent phenomenon. Thus, HSPs can be viewed as an important component of the multifactorial, complex response of cancer cells to CDDP. However, to strengthen such a conviction, more extensive studies are needed.

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Retinoic acid stimulates the synthesis of a novel heat shock protein in the regenerating forelimb of the newt

Biochemistry and Cell Biology ◽

10.1139/o93-007 ◽

1993 ◽

Vol 71 (1-2) ◽

pp. 43-50 ◽

Cited By ~ 5

Author(s):

Robert L. Carlone ◽

Robert P. Boulianne ◽

K. Marion Vijh ◽

Heather Karn ◽

Gordon A. D. Fraser

Keyword(s):

Retinoic Acid ◽

Heat Shock ◽

Stress Proteins ◽

Limb Regeneration ◽

Stress Protein ◽

Cross Reactivity ◽

Hsp 70 ◽

Peptide Map ◽

Shock Proteins

Morphogenetic effects of retinoic acid (RA) on the urodele amphibian limb regenerate pattern have been well documented, but little is known regarding the mechanism of this action of RA at the molecular level. Since exogenous RA, at concentrations sufficient to cause proximalization, represents a significant stress to newts and has been shown previously to elicit increased synthesis of heat shock proteins (HSPs) in mouse embryo limb buds, we investigated the effects of this putative morphogen on the synthesis of members of the 70-kilodalton (70-kDa) stress protein family in amputated forelimbs of the newt Notophthalmus viridescens. Injection (i.p.) of RA in dimethyl sulfoxide (DMSO), at a dose sufficient to cause significant proximal–distal reduplication of the pattern in 50% of animals treated, resulted in increased synthesis and accumulation of a 73-kDa protein with a pi of approximately 6.75. The synthesis of this same protein is increased in limb tissues as a result of a brief 35 °C heat shock. This protein is electrophoretically distinct from the newt HSP 70 family members, displays a different partial peptide map, and shows no immunological cross-reactivity with an anti-human HSP 70 monoclonal antibody. It may be a member of a separate family of 70- to 73-kDa HSPs. Interestingly, the synthesis of this protein is increased and it is more abundant in control, proximal moderate-early bud stage regenerates at 6 days after i.p. injection of DMSO than in similarly treated distal regenerates. This protein is, in addition, increased in distal regenerates to proximal levels by a prior injection of RA. The significance of these findings with regard to the possible role of stress proteins in the morphogenetic processes underlying limb regeneration is discussed.Key words: heat shock, limb regeneration, retinoic acid, pattern formation, newt.

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Radiation-Induced Stress Proteins - the Role of Heat Shock Proteins (HSP) in Anti- Tumor Responses

Current Medicinal Chemistry ◽

10.2174/092986712800099767 ◽

2012 ◽

Vol 19 (12) ◽

pp. 1765-1770 ◽

Cited By ~ 32

Author(s):

T.E. Schmid ◽

G. Multhoff

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Stress Proteins ◽

Induced Stress ◽

Radiation Induced ◽

Shock Proteins

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The Heat Shock Proteins are Novel Targets For Nobiletin in Human Cancer Cells

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.752.21 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

zili gao ◽

jinkai zheng ◽

Kalina Dimova ◽

Stylianos Scordilis ◽

hang xiao

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Cancer Cells ◽

Human Cancer ◽

Human Cancer Cells ◽

Novel Targets ◽

Shock Proteins

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The role of Hsp27 and actin in the regulation of movement in human cancer cells responding to heat shock

Cell Stress and Chaperones ◽

10.1007/s12192-008-0098-1 ◽

2009 ◽

Vol 14 (5) ◽

pp. 445-457 ◽

Cited By ~ 56

Author(s):

Bindi M. Doshi ◽

Lawrence E. Hightower ◽

Juliet Lee

Keyword(s):

Heat Shock ◽

Cancer Cells ◽

Human Cancer ◽

Human Cancer Cells

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Stimulation of survival capacity in heat shocked cells by subsequent exposure to minute amounts of chemical stressors; role of similarity in hsp-inducing effects

Human & Experimental Toxicology ◽

10.1191/096032799678840273 ◽

1999 ◽

Vol 18 (7) ◽

pp. 460-470 ◽

Cited By ~ 25

Author(s):

F A C Wiegant ◽

J E M Souren ◽

R van Wijk

Keyword(s):

Heat Shock ◽

Stress Proteins ◽

Low Doses ◽

Beneficial Effects ◽

Survival Capacity ◽

Subsequent Exposure ◽

Shock Proteins ◽

Degree Of Similarity ◽

Stimulation Of

1 A brief and moderate heat shock to Reuber H35 hepatoma cells causes a rapid increase in the synthesis of heat shock proteins (hsp) and initiates the development of thermotolerance, which results in an increased ability to survive exposure to otherwise lethal temperatures. 2 We now demonstrate that low doses of various chemical stressors (arsenite, cadmium, mercury, lead, copper, menadione and diethyldithiocarbamate (ddtc)), at concentrations that do not exert any effect in control cultures, are able to enhance the synthesis of hsps and to stimulate the development of thermotolerance when applied to cultures which were pretreated with a mild heat shock. 3 The degree of stimulation appears to be stressorspecific, which is not only observed in the ensuing development of thermotolerance but also in the enhancement of the heat shock-induced synthesis of stress proteins. 4 The different hsps that show an enhanced induction when heat shocked cultures are exposed to the various secondary applied low doses of chemical stressors, were found to resemble the hsp pattern that is characteristic for the secondary stressor and not for the initial heat shock. In other words, the nature of the post-treatment determines the observed pattern of enhanced synthesis of hsps. 5 In order to analyze the origin of the stimulation of survival capacity by low doses of the mentioned stressors, we studied whether the degree of stimulation is determined by the degree of similarity between the overall stress response to heat shock and to the second stress condition when applied singly. 6 The degree in which low doses of chemical stressors stimulate tolerance development and enhance the synthesis of hsps in cells that were previously heat shocked, appears to be related to the degree of similarity in the hsp pattern induced by both stressors. 7 Our results support the notion that low doses of toxic compounds may, under certain conditions, have beneficial effects related to a stimulation of endogenous cytoprotective mechanisms.

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Prospects of measuring stress proteins levels as markers of impaired adaptation in newborns

Practical medicine ◽

10.32000/2072-1757-2020-6-79-82 ◽

2020 ◽

Vol 18 (6) ◽

pp. 79-82

Author(s):

E. V. LOSKUTOVA ◽

◽

Kh. M. VAKHITOV ◽

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Stress Proteins ◽

Protective Role ◽

Regulation System ◽

Stress Reactions ◽

Nuclear Structures ◽

Shock Proteins ◽

Adaptive Reactions

The present literature review summarizes current information on the role of heat shock proteins in the genesis of physiological and pathological states in humans and animals. Their important role in controlling the process of proper protein folding into a spatial structure is noted, which is of key importance for the course of adaptive reactions. According to a number of sources, heat shock proteins also play a protective role in relation to the mitochondrial and nuclear structures of cells of various organs and systems. There is evidence of the heat shock proteins participation in the cytokine regulation system, the processes of peroxide homeostasis, energy exchange, etc. The authors suggest that studying their level in a premature newborn will create a more complete picture of the nature of stress reactions course and characteristics in the early neonatal period.

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