Heat shock proteins in prostate cancer: from tumorigenesis to the clinic

Figures & data

Table I.  New nomenclature of the main HSP (complete list in Kampinga et al. [13]).

Examples of old names	New name
Small heat shock proteins ⇒	HSPB
HSP27; HSP25; CMT2F ⇒	HSPB1
Crystalline alpha A; CRYAA ⇒	HSPB4
Crystalline alpha B; CRYAB ⇒	HSPB5
HSP20; FLJ32389 ⇒	HSPB6
HSP22; H11; HMN2 ⇒	HSPB8
HSP40 ⇒	DNAJ
DJ-2; DjA1; HSDJ ⇒	DNAJA1
HSP40; HSPF1 ⇒	DNAJB1
Hsc40 ⇒	DNAJB4
HSP70 ⇒	HSPA
HSP70-1; HSP72; HSPA1 ⇒	HSPA1A
BIP;GRP78; MIF2 ⇒	HSPA5
HSC70; HSC71; HSP71; HSP73 ⇒	HSPA8
HSP90 ⇒	HSPC
HSP90; HSP89; HSP90AA1 ⇒	HSPC1
HSP90-ALPHA; HSP90AA2 ⇒	HSPC2
HSP90-BETA; HSP90B ⇒	HSPC3
GRP94; GP96; TRA1 ⇒	HSPC4
HSP75; HSP90L; TRAP1 ⇒	HSPC5
HSP110 ⇒	HSP H
HSP105 ⇒	HSPH1
HSP110; HSPA4; APG-2 ⇒	HSPH2
HYOU1/Grp170; ORP150 ⇒	HSPH4
Chaperonins and related ⇒	HSPD and others
HSP60; GroEL ⇒	HSPD1
HSP10; chaperonin 10; GroES ⇒	HSPE1
TCP1; CCTA; CCT-alpha ⇒	CCT1
McKusick-Kaufman syndrome ⇒	MKKS
Bardet-Biedl syndrome 10 ⇒	BBS10

Figure 1. Schematic representation of the HSP response and the implications of these proteins in cell functions. The numerous roles of this superfamily of proteins may explain that, during evolution, gene duplication appeared as a mode of adaptation providing the cells with the functionality of the HSP. HSFs: Heat Shock Factors.

Table II.  Studies evaluating HSP during the tumorigenesis of prostate cancer.

Molecule	Status/level of gene/protein expression	Authors
HSP (S)	In NP-LPC transition, 16 hsp genes were differentially expressed: 9 (56%) were up-regulated and 7 (44%) were down-regulated. In the LPC-MPC transition, 14 genes were differentially expressed; 10 of them (71%) were up-regulated	Byun et al. [50]
	Differential expression in PC compared to BPH	Ummanni et al. [51]
	Different post-translationally modified isoforms of HSPB1 and HSPA1A in PNB specimens from patients with PC or BPH	Lin et al. [52]
HSPC4	Reduced expression in PC compared with benign prostate tissue (BPH). A trend for correlation between low HSPC4 and high Gleason score, supported the hypothesis that HSPC4 suppression correlates with CTC formation and metastasis.	Howard et al. [53]
HSPC	Strong expression in 95% of PIN and carcinomas without relationship with Gleason score.	Elmore et al. [54]
	Higher immunoreactivity in PC and PIN than in NPA In the epithelium and stroma increased expression from NAP to PIN to PC.	Cardillo et al. [55]
HSPA	Higher expression in cancer tissue than in normal tissue	Mori et al. [56]
	HSPA1L polymorphism may be associated with a protection against PC development.	Sfar et al. [57]
	Over-expressed in PC compared with benign prostate samples.	Lexander et al. [58]
HSPD1/E1 Complex	High cytoplasmic positivity for both of these markers was present in PIN lesions as well as in carcinomas.	Capello et al. [59]
	Over-expressed in PC compared with benign prostate samples.	Lexander et al. [58]
HSPB1	The expression level highly correlated with the progression from BPH to PC, with tumour grade and stages.	Zhen et al. [60]
HSPA/HSPC Cochaperone alphaSGT	Higher AR/alphaSGT ratio en MPC samples.	Buchanan et al. [61]

(S), several; NP, normal prostate; LPC, localised prostate cancer; MPC, metastatic prostate cancer; PIN, prostatic intraepithelial neoplasia; PC, prostate cancer; BPH, benign prostate hyperplasia; PNB, prostate needle biopsy; CTC, circulating tumour cells; NPA, normal prostatic tissue adjacent to neoplasia; AR, androgen receptor; alphaSGT, small glutamine-rich tetratricopeptide repeat containing protein alpha.

Table III.  Studies evaluating HSP in the prognosis of prostate cancer patients.

HSP	Patients	Significance	Authors
HSPB1	97 (NHT*)	>HSPB1 after NHT Associated with Gleason score >HSPB1 < biochemical RFS but not an independent predictor	Miyake et al. [63]
	172	Associated with Gleason score, with lymph node metastasis and others >HSPB1 < biochemical RFS but not an independent predictor	Kurahashi et al. [64]
	289	Associated with Gleason score >HSPB1 < biochemical RFS but not an independent predictor	Glaessgen et al. [65]
	193	>HSPB1 < biochemical RFS but not an independent predictor	Miyake et al. [63]
HSPA5	219(T3N oM0)	Associated with castration resistance >HSPA5 > recurrence, < OS	Pootrakul et al. [66]
	153 (LN+)	>HSPA5 > recurrence, < OS	Daneshmand et al. [67]
HSPD1	289	Associated with Gleason score >HSPD1 > biochemical recurrence independent predictor	Glaessgen et al. [65]
HSPA1A HSPC1	172	Not associated with CP factors Lack of prognostic significance	Kurahashi et al. [64]
	193	Not prognostic significance	Miyake et al. [68]
HSPA1A	289	Not associated with Gleason score Lack of prognostic significance	Glaessgen et al. [65]
Clusterin	See review	Associated with pathological grade and biochemical recurrence	So et al. [69]

NHT, neoadjuvant hormonal therapy (HSPB1 was studied comparing pre- and post-NHT); RFS, relapse-free survival; OS, overall survival; LN+, lymph node-positive (D1 disease stage); CP, clinicopathological factors.

Biochemical recurrence evaluated by serum levels of PSA.

Figure 2. Examples of the expression of HSP in prostate tissues. In a patient with an early tumour (PIN in a tru-cut biopsy), the cytokeratin 7 (A) shows the basal cells in the normal gland while in the PIN (right side) these cells are lacking and there is aberrant cytokeratin 7 expression in a tumour cell clone (note the brown positive immunoreaction, diaminobenzidine). In the serial section, HSPB1 appears in the stroma and with weak immunoreactivity in the normal gland but is absent in the PIN cells (B). In contrast, HSF1 and several HSP appear in the cancer tissue from a patient with advanced disease (metastasis in a cervical lymph node). This patient failed to respond to the GnRH agonist treatment and to suffered bone metastases. (C) note the variable expression of HSPB1 in cancer cells; (D) HSPA1A and HSPA8 (these two forms are recognised by the BRM22 monoclonal antibody) appear in the nuclei and cytoplasm in the tumour cell clusters; (E) HSF1 in the nuclei of the tumour cells; (F) HSPD1 in the cytoplasm of tumour cells; and (G) HSPA5. Original magnification ×30 (A, B), ×120 (C–G). The tissues were lightly counterstained with haematoxylin to reveal nuclei.

Table IV.  Targeting HSP in prostate cancer.

Chaperone-client protein interactions ⇒ protection of the client from degradation

HSPC1 with: AR*, mutated p53, Her-2/neu, Akt, CDK4, C-Raf, Bcr-Abl, etc.

Interfering with: geldanamycin, 17-AAG, 17-AAG analogues and others [72–77]

HSPB1 with Stat3 ⇒ suppression of apoptosis [78]

HSPB1 with Her-2/neu ⇒ resistance to MAb treatment [79]

Interfering with: ASO, short interfering RNA

HSP-based immunotherapy ⇒ autoimmune response ⇒ rejection of tumor cells

Using HSPC4, HSPA1A, HSPH4, clusterin, others [80–85]

HSP dosimetry ⇒ HSP expression kinetics and injury data ⇒ maximize tumour destruction minimise healthy tissue injury [86]

AR, androgen receptor; MAb, immunotherapy with humanized monoclonal antibody; ASO, antisense oligonucleotides.

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