The role of heat shock proteins in cancer

ARTICLE IN PRESS Cancer Letters ■■ (2015) ■■–■■

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Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

The role of heat shock proteins in cancer Georgios D. Lianos a,b,1, George A. Alexiou a,b,1, Alberto Mangano c, Alessandro Mangano c, Stefano Rausei c, Luigi Boni c, Gianlorenzo Dionigi c, Dimitrios H. Roukos a,b,* a b c

Centre for Biosystems and Genomic Network Medicine – CBS. GenNetMed, University of Ioannina, Ioannina, GR 451 10, Greece Department of Surgery, University of Ioannina, Ioannina, GR 451 10, Greece Department of Surgical Sciences and Human Morphology, University of Insubria, Varese, Italy

A R T I C L E

I N F O

Article history: Received 9 December 2014 Received in revised form 10 February 2015 Accepted 12 February 2015 Keywords: HSPs Tumor biomarkers Targeted agents Personalized cancer medicine HSP90

A B S T R A C T

Heat shock proteins (HSPs) are an evolutionary family of proteins that act as molecular chaperones. According to their size they have been classified into the following families; HSP90, HSP70, HSP60, HSP40 and HSP27. They prevent the formation of nonspecific protein aggregates and they assist proteins in the acquisition of their normal architecture. Moreover, HSPs are likely to have anti-apoptotic properties and are actively involved in various processes as tumor cell proliferation, invasion, metastases and death. Notably, these proteins have been reported to be significantly elevated in a plethora of human cancers. Their overexpression has been robustly associated with therapeutic resistance and poor survival. In this way, HSPs may have important therapeutic implications and they can be targeted by specific drugs. In this review, we discuss the influence of HSP27, HSP40, HSP60, HSP70 and HSP90 on human cancers. In addition, we report the existing scientific data on this issue with an effort to highlight the possible future implication of HSPs as tumor biomarkers or drug targets for improving prognosis and treatment of cancer patients around the world. © 2015 Elsevier Ireland Ltd. All rights reserved.

Introduction HSPs are polypeptides-proteins and most of them perform essential functions. Most famous is their role as molecular chaperones [1]. Thus, these polypeptides are actively involved in the synthesis and folding of proteins throughout the cell. In other words, HSPs are highly conserved molecular chaperones that are synthesized and expressed by the cell in response to stress conditions [2]. HSPs have been classified according to their size into: HSP90, HSP70, HSP60, HSP40 and small HSPs including HSP27 [3]. In addition, HSPs have been shown to participate in various important processes such as protein assembly, secretion, trafficking, protein degradation and regulation of transcription factors. It is also described that HSPs are essential proteins that play a crucial role in cell survival because they are responsible for many cytoprotective mechanisms [4]. Recent studies have shown that HSPs (discovered for the first time in 1962) are often highly expressed in various types of cancers [5–7]. They are induced by different stress signals and they interestingly promote cell survival in various conditions. For these reasons, the role of HSPs has been the object of focused and extensive research in several conditions where these proteins accumulate, such as in cancer. Recent evidence support that HSPs are actively

* Corresponding author. Tel.: +302651007423; fax: +302651007094. E-mail address: [email protected] (D.H. Roukos). 1 Equally contributed to the manuscript.

involved in tumor cell proliferation, invasion, differentiation, metastases and death. The most important point is that these proteins resulted over-expressed in a plethora of tumors [8]. For example in prostate cancer, androgen receptors are implicated in tumorigenesis and progression. HSP27 regulates the androgen receptor’s stability, nuclear shuttling and transcriptional activity [9,10]. Furthermore, Hsp27 is required for epidermal growth factor-mediated epithelial to mesenchymal transition via modulation of the β-catenin/ Slug signaling pathway [11]. HSP70 and HSP90 interact with WASF3 which is involved in prostate cancer invasion and metastasis [12]. Finally, HSP40 is involved in prostate cancer progression, since it inhibits apoptosis through the complex of Hsp70, Fanconi anemia group C protein and dependent protein kinase (PKR) [13]. With this article we provide a comprehensive review on the current status of the association of HSP27, HSP40, HSP60, HSP70 and HSP90 with cancer and we examine their possible future implication as appropriate targets for modulating cell death pathways. Moreover, we report the available data for their possible use as valuable tumor markers in the near future in order to reach the distant goal of true personalized cancer medicine. HSP27 HSP27 is a member of the small HSP family and acts as an ATP-independent chaperone. It is reported that this protein was characterized for the first time in response to heat shock as a protein chaperone that facilitates the refolding of damaged proteins [14].

http://dx.doi.org/10.1016/j.canlet.2015.02.026 0304-3835/© 2015 Elsevier Ireland Ltd. All rights reserved.

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This protein resides mainly in the cytosol [15]. Notably, HSP27 has also a potent antioxidant and anti-apoptotic property. It is also involved in cell migration, in architecture of cytoskeleton, cell growth, differentiation, and tumor progression. In each of these processes, HSP27 has been involved and implicated in different disease pathways having both protective and counter-protective capacities [16]. Continued intensive research revealed that HSP27 responds to stress conditions other than heat shock. HSP27 responds also in conditions of oxidative stress and chemical stress as well. In oxidative stress environment, HSP27 has an antioxidant capacity. It seems that HSP27 act lowering the concentration of reactive oxygen species by raising the intracellular glutathione levels and by lowering the intracellular iron concentration. During chemical stress, HSP27 has antiapoptotic properties and functions by interacting with mitochondrial dependent and independent apoptosis steps. It is also reported to be involved in protection from the programmed cell death. This is possible by inhibition of caspase-dependent apoptosis [17]. In the Oncology field, HSP27 has been found to be present in the intracellular and the extracellular environment. There are studies that showed an increased level of HSP27 in various types of cancer such as ovarian, prostate, brain and breast cancers [18]. As for brain tumors, it is reported that HSP27 expression was correlated with histological grades of astrocytoma and with Ki-67 index [19]. Regarding meningiomas, an immunohistochemical study revealed low HSP27 cytoplasmic immunoreactivity in 26 of 64 cases of meningiomas encountered in the study. Using Western blotting, some researchers detected the presence of HSP27 in every meningioma tissue of the cases studied [20]. Overexpression of HSP27 was found to be associated with poor prognosis for these patients with meningiomas. Moreover, it has been proven that HSP27 accumulation reduces the apoptotic process induced by alkylating agents in colorectal cancer cells [21]. Recently, HSP27 has also been object of research in order to elucidate its possible contribute to invasion and metastasis cascade affecting the overall survival of the patients. And the question is obvious. Could HSP27 be used as a biomarker for the diagnosis of some types of human cancer? In a recent study from patients with prostate cancer, the expression of intracellular HSP27 was analyzed and reported. The researchers observed that HSP27 expression in prostate cancer tissue group was over-expressed when compared to the control group [22]. Similar important studies were also conducted in women with breast cancer. HSP27 levels in serum and in tumor microenvironment were determined and analyzed by ELISA. These studies showed that serum levels of HSP27 were significantly higher in the breast cancer patients group compared to the control group. Furthermore, another important point of these studies was that HSP27 levels released directly by breast tumor cells were significantly higher than the HSP27 serum levels [23]. Another study in women with breast cancer showed that HSP27 levels in the interstitial fluid isolated from primary breast tumor tissue could be surprisingly high [24]. Recent research exist about the possible association of HSP27 levels with poor prognosis in many other types of cancer such as gastric, liver, prostate, lung and colorectal cancer. An important study was recently conducted to characterize HSP27 concentrations in patients with colorectal cancer. The authors concluded that HSP27 expression was not correlated with overall survival (OS) in patients with colon cancer. On the other hand, HSP27 expression was strongly correlated with poor survival and with non clear margins of resection in patients with rectal tumors [25]. Some researchers agree that HSP27 may be also involved in resistance to chemotherapy in patients with breast cancer and in patients with leukemia. On the other hand, other researchers report that HSPs in general and especially HSP27 can also represent the ideal targets for cancer therapy treatment with appropriate drugs, as well as targets for the immune system. In this pathway it seems that the massive release of HSP due to tumor cell necrosis after cytotoxic drugs can lead to

CD8 +T cell mediated anti-tumor immune answers [26]. A recent study compared HSP27 expression in patients with esophageal adenocarcinoma who were responsive and non-responsive to neoadjuvant chemotherapy including platin and 5-fluorouracil. The authors concluded that low HSP27 expression was associated with non-responsiveness to the chemotherapy treatment [27]. Nowadays there are some preliminary trials, using as target HSP27 in cancer therapy primarily through the down-regulation of HSP27. The researchers revealed that while traditional chemotherapeutic agents were able to modestly reduce tumor volume, adding the HSP27 inhibitor (quecertin) resulted in a surprising reduction of tumor dimensions. Several studies revealed that overexpression of HSP27 may be correlated with increased resistance to chemotherapeutic drugcaused apoptosis in tumor cells [28]. In this way Hansen et al. has reported the inhibition of doxorubicin induced apoptosis in breast cancer cells that present overexpression of HSP27. Is also demonstrated a crucial protective role of HSP27 against apoptosis process. In addition, a recent important study presented that upregulation of HSP27 in breast cancer cells reduces trastuzumab susceptibility by increasing HER2 protein stability [29]. These recent studies suggest the possibility of HSP27 inhibition for molecular target for cancer therapy. However it is believed that, unlike other HSPs, the small HSPs as HSP27 do not bind ATP, and this makes HSP27 difficult for representing an ‘easy target’ for the small compounds [30]. It is obvious that researchers should focus in this way in the next years in order to provide promising results in cancer treatment field. HSP40 HSP40 represents a large and understudied family of cochaperones. Human genome codes for over 41 members of this HSP40 family. These members are believed to reside in different intracellular sites [31]. It is reported that the HSP40 family, also known as chaperone DnaJ, regulates HSP70 function. It seems that HSP90 and the HSP40–HSP70 complex act together to enhance the Akt pathway which represents a known and essential cell survival pathway. Current knowledge about the association of the HSP40 family with human cancers is very restricted and controversial. Recent evidence showed that HSPs are overexpressed in a plethora of human cancers, conferring potential resistance to cytotoxic management [32]. A recent study revealed parallel high expression of HSP40, HSP70 and HSP90 in brain tumors. Moreover, a study on lung cancer tissues showed that HSP40 was highly expressed. In addition, this study revealed that levels of HSP40 from the serum of cancer patients, detected using anti-HSP antibodies, can be used in tumor diagnosis. Interestingly, as mentioned above, genome-wide analysis revealed 41 DnaJ–HSP40 family members in humans that may be responsible for vital functions. These proteins are localized in different intracellular sites such as mitochondria, cytosol, endoplasmic reticulum, endosome, nuclei and ribosomes [33]. In recent years the possible involvement of the HSP40 family in tumorigenesis and malignant processes has been a matter of debate. Is widely known that metastatic progression is a process by which tumor cells from one location of the body move to another site, find a suitable ambient and begin to multiply. Cells from the original or primary tumor must enter the appropriate lymphatic “road” or the blood vessels so that they can be carried through the body. Some reports are describing the involvement of some HSP40 family members, such as hTid 1 (class DNAJA3) and HLJ1 (class DNAJB4) in the modulation of tumor growth [33]. These findings are shaping now new and promising roadmaps in the clinical oncology setting. Wang et al. identified HLJ1 (DNAJB4), revealing that its expression was inversely correlated with cancer cell invasion capacities. This was achieved comparing gene expression profiles of invasive and metastatic lung cell lines such as CL1-0, CL1-1, CL1-5 and

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CL1-5-F4 in order of increasing invasion potential. This was a very important result and the same study reported also a straight correlation of the increased HLJ1 with E-cadherin expression [34]. After this study, Tsai et al. have studied again the role of HLJ1 in tumor suppression of non-small-lung cancer cells with the same results. HSP40 has been studied also in skin cancer, colon cancer and in gliomas [35]. Furthermore, some studies showed that overexpression of hTid-1 led to inhibition of cell proliferation and induction of apoptosis of A375 human melanoma cells as well as in human osteosarcoma [36]. As for breast cancer, a recent study determined transcriptome changes in human breast cancer progression using analysis of gene expression. This study highlights MRJ (DNAJB6) as one of the most frequently under-expressed genes between normal breast epithelium and ductal carcinoma in situ (DCIS) [37]. In addition, a recent study concluded that the progression of colorectal cancer is associated with over-expression of hTid-1. This study proved that hTid-1 acts as a ligand of the famous APC gene (adenomatosous polyposis coli) [35]. To our knowledge, these members of the HSP40 family (HLJ1, Tid1 and MRJ(L)) are the more studied members for their possible implication on cancer ‘behavior’. More studies are needed to clarify the role of other HSP40 family members that are likely to play a crucial role in cancer. We have to mention here a recent study showed that 5-fluorouracil (5-FU) and carboplatin induce expression of HSP40 in addition to HSP27 in Hep3B and HepG2 cells. However is believed that, under lethal conditions with reduced cell viability, cells are not able to receive the induction signal of survival proteins such as HSP27 and HSP40. It is known that the increased cell death correlates with decreased levels of procaspase3. Furthermore, siRNA mediated knockdown of HSP27 and HSP40 decreases survival of drugs exposed cells. Inhibition of the expression of HSP27 and HSP40 does not allow cells to adapt to drug exposure and have the chance to survive. The action of 5-FU or carboplatin following knockdown of HSP27 and HSP40 highlights their potential strategic role toward an effective therapy against hepatocellular carcinoma [38]. Results suggest that inhibition of HSP40 and HSP27 potentiates the role of 5-FU and carboplatin in hepatoma cell killing. It is obvious that further understanding of the role of HSP40 family members in cancer biology is important and may lead to discoveries of novel signaling pathways and targets for possible cancer treatment. HSP60 HSP60, called also chaperonin, was one of the first heat shock proteins studied. HSP60 plays an essential role in the transport and folding of mitochondrial proteins, and is reported to be associated with different types of cancer [39]. To date, the role of HSP60 in brain tumors has not been fully elucidated. A famous study by Xanthoudakis et al. [40] reported that HSP60 has a pro-apoptotic role by facilitating the activation of pro-caspase-3 by different caspases, including caspase-6. Moreover, HSP60 situated in cytosol prevents the translocation of the pro-apoptotic protein Bax into mitochondria and in this way promotes cell survival [40]. Ghosh et al. reported that HSP60 is up-regulated in human cancers including some cases of glioblastoma [41]. Recently, HSP60 and its prognostic association with cervical cancer represents a great topic of research. In these studies, the prognostic value of HSP60 in cervical cancer was evaluated by 2-Dimensional Electrophoresis (2-DE), semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and Western Blot (WB) analyses. The results significantly suggest that HSP60 plays a crucial role in the development of cervical cancer. Hwang et al.’s study confirmed the upregulated expression of HSP60 in cervical cancer [42]. Moreover, data from patients with advanced prostate cancer showed a significant correlation between HSP60 expression and tumor progression. HSP60

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expression was also reported to be highly associated with androgen independence in the group of locally advanced prostate cancers. Moreover, the intensity and extent of immunoreactivity of HSP60 predicted biochemical recurrence in patients with prostate cancer. Another important finding of this study was that patients with intense HSP60 staining in biopsy presented shorter recurrencefree survival than patients with weak HSP60 expression. Another study performed in patients with prostate cancers showed that HSP60 expression increases in prostate cancer tissues when compared with normal prostatic tissue [43]. In breast cancer research, studies proved the presence of autoantibodies anti-HSP60 and the concentration of serum HSP60 antibodies was significantly associated with cancer grade. Interestingly, high grade tumors showed elevated levels of HSP60 autoantibodies. On the other hand, low-grade breast tumors were associated with non-elevated levels of HSP60. In addition, other analyses performed on breast cancer tissues showed elevated expression of HSP60 in advanced stage tumors. These results support the idea that HSP60 overexpression in the initial stages may be relevant for the early diagnosis of breast cancer [44]. HSP60 was also found by serum antibodies in patients with liver cirrhosis and hepatocellular carcinoma [45]. Moreover, in patients with colorectal cancer, the overexpression of HSP60 showed a significant correlation with tumor differentiation and may also have an important prognostic impact on survival. In their effort to identify possible new serum biomarkers for colorectal carcinoma, the researchers performed an important study. They compared colon tumor tissues with normal tissues from 15 patients with colorectal cancer. They used two dimensional difference gel electrophoresis (2D-DIGE). They identified a total of 17 proteins that presented significant differential expression. Their results were confirmed by WB analyses for HSP60, glutathione-Stransferase Pi, T-complex protein 1 subunit b, and leukocyte elastase inhibitor. Immunohistochemistry was used for HSP60. They concluded that elevated concentrations of HSP60 were found in serum from patients with colorectal cancer. Moreover, serum HSP60 levels appeared to be more specific for late-stage colorectal cancer [46]. During a Greek study performed by Giaginis et al., HSP27, HSP60, and HSP90 expression was studied in tumor tissues of 66 patients with gastric adenocarcinoma. The results were elaborated in relationship with clinico-pathological characteristics, proliferative tumor potential and patients’ overall survival rates. HSP60, HSP27 and HSP90 proteins were surprisingly highly expressed in gastric adenocarcinoma tissues. HSP27 expression was associated with tumor size, the presence of organ metastases and final stage. As for HSP60, its expression was correlated with the patient’s gender. HSP60 expressed intensity was associated with patients’ age and tumors’ grade. On the other hand, elevated HSP90 expression was associated significantly with longer overall survival in univariate and multivariate analyses. Thus, the authors conclude that HSP90 is an independent prognostic factor of survival in patients with gastric adenocarcinoma. This conclusion is to be confirmed with further studies [47]. As for the impact of HSP60 on metastasis cascade current evidence is limited. All the researchers agree that aberrant activation of b-catenin constitutes the cornerstone of tumorigenesis and metastasis. A study showed that overexpression of HSP60 induces metastatic phenotypes. The b-catenin activation was shown to be related to different types of metastatic cancer such as colorectal, lung, prostate and ovarian metastases. In addition, b-catenin activation led to invasion and was associated with epithelial transition, a mechanism essential for metastasis. HSP60 increases the concentration of b-catenin protein. Proteosomal activity is not necessary for the induction of b-catenin by HSP60. Is believed that co-expression of HSP60 and b-catenin predicts poor prognosis in patients with metastatic head and neck tumors [48]. These results implicate a potential

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crucial role of HSP60 in metastasis. Further studies are needed in order to illustrate possible implications and applications for making early cancer diagnoses, improving prognosis throughout response to therapy, and developing novel anti-cancer treatment guidelines. HSP70 At least eight members of the HSP70 family have been reported and implicated in cancer initiation and progression, not only because of their function as a chaperone but also for cell signaling regulation, namely co-chaperone Bag3 [49]. In several cancers, HSP70 overexpression correlated with increased cell proliferation rate and malignancy [50–52]. In medulloblastomas a significant positive correlation between Ki-67 index and aggressive subtype has been recently reported [51]. HSP70 knockdown enhanced chemosensitivity to certain chemotherapeutic regimens in several malignancies [50]. Overexpression of HSP70 is a marker for advanced disease and poor prognosis in colon cancer, breast cancer, melanoma and bladder cancer [53]. An insight into the molecular mechanisms that are involved in HSP70 and cancer reveals several checkpoints in which HSP70 has a pivotal role. HSP70 can inhibit apoptosis in multiple points. In the intrinsic pathway HSP70 inhibits Bax activation and therefore prevents the mitochondrial membrane permeabilization and release of proapoptotic factors [54]. Regarding extrinsic pathway, HSP70 inhibits assembly of death-inducing signaling complex (DISC) [55]. Senescence is a state in which cells stop to divide, and has been considered a weapon for cancer treatment. Downregulation of Hsp72 in certain cancer lines induced cell senescence via p53-dependent and p53-independent pathways [56]. Bag3 is a nucleotide exchange factor of the heat shock protein Hsp70. The Hsp70–Bag3 has been recently reported to modulate the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin [57]. BAG3 has been also associated with authophagic cell death. Furthermore, HSP70 has a crucial role in maintaining DNA integrity by binding to poly (ADPribose) polymerase-1 (PARP-1). HSP70 plays a role at the base pair excision system. DNA-damaging agents have a long history of use in cancer chemotherapy; thus research for inhibition of cancer cell DNA repair involving HSP70 is warranted [58]. Based on the above, HSP70 has been considered an ideal target for cancer treatment. Several inhibitors have been reported, however few have been evaluated in in vivo studies. PES-Cl, MKT-077 and Ver-155008 have been reported to have significant anticancer activity. In a recent comparative study these three regimens could inhibit autophagy and induced reduced levels of HSP90 client proteins. Nevertheless, only PES-Cl could inhibit the APC/C and induce G2/M arrest [59]. HSP90 HSP90 is another anti-apoptotic protein, associated with a number of signaling pathways and the most well studied member of the heat shock protein family. HSP90 functions together with HSP70 and HSP40 [60]. HSP90a has been found elevated in medulloblastoma, the most malignant pediatric brain tumor. Furthermore, a significant positive correlation between the expression of HSP70 and HSP90 was found in this tumor [52]. In breast cancer significant increased expression has been found in ductal carcinomas, whereas decreased immunohistochemical expression was found in lobular carcinomas [61]. In colorectal cancer, epithelial to mesenchymal transition constitutes a major step for metastasis induction. Inhibition of the HSP90 in turn downregulated HIF-1α and NF-κB and resulted in inhibition of EMT, invasion, and motility of cancer cell lines [62]. Interplay between HSP90 and other co-chaperones, such as Hop, p23, Cdc37, Aha1, and PP5 has been extensively studied [63]. Since HSP90 has a pivotal role in malignant transformation, it has been

considered a promising target for cancer therapy. Several HSP90 inhibitors are under investigation for cancer treatment, targeting the N-terminus or the C-terminus of the protein. Retaspimycin hydrochloride (IPI-504), a derivative of geldanamycin and 17-AAG, has been found generally well tolerated and proven to be effective in glioma cell lines, however a modest suppression of tumor growth in immunocompromised mice was reported [64]. AUY922, a recently developed HSP90-inhibitor, suppressed in vitro cell growth of islet neoplasms in a dose-dependent manner and in an in-vivo mouse model significantly reduced tumor volume by 92% compared to control and increased survival [65]. Chemoresistance is a major obstacle in cancer treatment and is usually mediated by p-glycoprotein expression and multidrug resistance proteins (MRP), which are transmembrane drug efflux pumps [66]. Increased expression of these proteins has been associated with resistance to Hsp90 inhibitor and is also a matter of research. Conclusion HSPs are a family of proteins that serve as molecular chaperones and are highly expressed in several malignancies. They have been associated with cancer progression, response to treatment and patients’ overall prognosis. Thus, over the last decade extensive research has been conducted toward the development of specific HSP inhibitors. Among them, the most promising constitutes the HSP90 inhibitors, since they can inhibit several oncogenic proteins. Based on the above, several clinical trials with HSP inhibitors are currently under way and the results are expected with great interest. Funding None. Conflict of interest None. References [1] G. Jego, A. Hazoumé, R. Seigneuric, C. Garrido, Targeting heat shock in cancer, Cancer Lett. 332 (2013) 275–285. [2] A. Vidyasagar, N.A. Wilson, A. Djamali, Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target, Fibrogenesis Tissue Repair 5 (2012) 7. [3] R. Seigneuric, H. Mjahed, J. Gobbo, et al., Heat shock proteins as danger signals for cancer detection, Front. Oncol. 1 (2011) 37. [4] H.H. Kampinga, J. Hageman, M.J. Vos, et al., Guidelines for the nomenclature of the human heat shock proteins, Cell Stress Chaperones 14 (2009) 105–111. [5] H. Ledford, Cancer theory faces doubts, Nature 472 (2011) 273. [6] L. Moran, M.E. Mirault, A.P. Arrigo, M. Goldschmidt-Clermont, A. Tissieres, Heat shock of Drosophila melanogaster induces the synthesis of new messenger RNAs and proteins, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 283 (1978) 391–406. [7] F. Ritossa, A new puffing pattern induced by temperature shock and DNP in drosophila, Cell. Mol. Life Sci. 18 (1962) 571–573. [8] A.L. Joly, G. Wettstein, G. Mignot, F. Ghiringhelli, C. Garrido, Dual role of heat shock proteins as regulators of apoptosis and innate immunity, J. Innate Immun. 2 (2010) 238–247. [9] S. Hassan, M.H. Biswas, C. Zhang, C. Du, K.C. Balaji, Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells, Oncogene 28 (2009) 4386–4396. [10] A.A. Azad, A. Zoubeidi, M.E. Gleave, K.N. Chi, Targeting heat shock proteins in metastatic castration-resistant prostate cancer, Nat. Rev. Urol. 12 (1) (2015) 26–36. [11] T. Cordonnier, J.L. Bishop, M. Shiota, K.M. Nip, D. Thaper, S. Vahid, et al., Hsp27 regulates EGF/β-catenin mediated epithelial to mesenchymal transition in prostate cancer, Int. J. Cancer 136 (6) (2015) E496–E507. [12] Y. Teng, L. Ngoka, Y. Mei, L. Lesoon, J.K. Cowell, HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein, J. Biol. Chem. 287 (13) (2012) 10051–10059. [13] Q. Pang, T.A. Christianson, W. Keeble, T. Koretsky, G.C. Bagby, The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC, J. Biol. Chem. 277 (51) (2002) 49638–49643.

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Please cite this article in press as: Georgios D. Lianos, et al., The role of heat shock proteins in cancer, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.02.026