Journal of Cancer Research and Therapeutics

: 2013  |  Volume : 9  |  Issue : 4  |  Page : 583--586

Emphasizing on heat shock protein 90's utility in head and neck squamous cell carcinoma treatment

Samapika Routray1, Aparajita Sunkavalli2, Niharika Swain3, Akhil A Shankar4,  
1 Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Bhubaneswar, Odisha, India
2 Department of Periodontics, GITAM Dental College and Hospital, Rushikonda, Vishakhapatnam, Andhra Pradesh, India
3 Department of Oral Pathology and Microbiology,MGM Dental College and Hospital, Kharghar, Navi Mumbai, Maharashtra, India
4 Department of Oral Pathology and Microbiology,Y.M.T. Dental College, Kharghar, Navi Mumbai, Maharashtra, India

Correspondence Address:
Samapika Routray
Department of Oral Pathology and Microbiology, Institute of Dental Sciences, «SQ»SOA«SQ» University, Sector 8, Ghatikia, Bhubaneswar, Odisha - 751 003


Heat shock protein 90 (Hsp90) a member of the heat shock proteins (HSPs) family, is an adenosine triphosphate dependent molecular chaperone protein, which integrates multiple oncogenic pathways. Clinically, encouraging results have been demonstrated in melanoma, acute myeloid leukemia, castrate refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma using the first generation Hsp90 inhibitors. Hsp90 as the target of anticancer activity of geldanamycin sparked much interest in the inhibition of Hsp90 as a strategy for the treatment of cancer. Hsp90 inhibitors demonstrate rapid clearance from normal tissues and the blood compartment with prolonged retention in tumors making it a sought after modality for treating cancer. Our review emphasizes its role as anti-cancer therapy for head and neck squamous cell carcinoma.

How to cite this article:
Routray S, Sunkavalli A, Swain N, Shankar AA. Emphasizing on heat shock protein 90's utility in head and neck squamous cell carcinoma treatment.J Can Res Ther 2013;9:583-586

How to cite this URL:
Routray S, Sunkavalli A, Swain N, Shankar AA. Emphasizing on heat shock protein 90's utility in head and neck squamous cell carcinoma treatment. J Can Res Ther [serial online] 2013 [cited 2020 Aug 6 ];9:583-586
Available from:

Full Text


First discovered by Ferruccio Ritossa in 1962, the hypothesis still stands sturdy that a cell when subjected to environmental stress undergoes a response known as heat shock response. It has also been established that during this heat shock response, stress proteins or heat shock proteins (HSPs), are articulated. These HSPs were considere d to be molecular chaperones defined as "proteins that bind to and stabilize an otherwise unstable conformer of another protein and by controlled binding and release, facilitate its correct fate in vivo: Be it folding, oligomeric assembly, transport to a particular subcellular compartment or disposal by degradation." [1] Later Schlesinger in 1990, further added that these proteins are protective cellular proteins by nature and are named so because heat, environmental stressors (metabolic poisons, heavy metals), oxidants, internal stress, viral, microbial infections, inflammation, ischemia, induce its production. [2]

In an overview by Scully and Bagan about the head and neck squamous cell carcinoma (HNSCC), its highlighted that oral keratinocyte is the cell of origin and it is initiated by deoxyribonucleic acid (DNA) mutation. [3] Similarly Haddad and Shin, described molecular basis of HNSCC, as a multistep process, where this whole progression undergoes genetic instabilities including the loss of heterozygosity of certain chromosomes (3p14, 9p21, 17p13, 8p, 11q, 13q, 14q, 6p, 4q27 and 10q23) and amplification or deletion or up-regulation or down-regulation of certain oncogenes or tumor-suppressor genes, including epidermal growth factor receptor (EGFR), p53, Rb, p65, cyclooxygenase-2 (COX-2), p16, cyclin D1, etc., For metastasis and tumor progression, the genes mainly involved are those encoding E-cadherin (CDH1), chemokine (C-X-C motif) receptor-stromal-cell-derived factor 1 (CXCR4-SDF-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor (TGF-α and TGF-β), interleukin-8 (IL-8), and matrix metalloproteinase (MMP). [4]

Taking into consideration the fact that HNSCC is a genetic disease and is preceded by the gamut of changes in both genetic and metabolic levels we hereby emphasis on a particular molecular chaperone heat shock protein 90 (Hsp90) for its role in diagnosis and therapy. These molecular chaperone Hsp90 use by cancer cells to facilitate the function of numerous oncoproteins has been long-established. Our effort in this review is to understand the complexity of Hsp90 regulation and its involvement in both normal cellular physiology and HNSCC.

 Heat Shock Proteins

HSPs have been classified into six families according to their molecular size: Hsp100, Hsp90, Hsp70, Hsp60, Hsp40 and small HSPs (15-30 kDa) including Hsp27. High molecular weight HSPs are adenosine triphosphate (ATP)-dependent chaperones while small HSPs act in an ATP-independent fashion. [5] Hsp's 28, 40, 70 and 110 genes to be mostly evolved from a highly efficient mechanism for mass synthesis during stress, with powerful transcriptional activation, efficient messenger ribonucleic acid (mRNA) stabilization and selective mRNA translation whereas Hsp's 27, 70, 90 and 110 increase to become the dominantly expressed proteins after stress. [6] In the late 1900s several authors described the roles of these chaperones distinctively. Small HSPs are phosphorylated by stress-kinases and in turn they increase the amount of reduced glutathione in the cytoplasm. [7] Hsp60 (liberated after the disruption of mitochondrial membrane), promotes apoptosis by activating caspases. [8] Gabai et al. (1998) [9] concluded that Hsp70 protects cells against oxidative stress and inhibits stress kinases and apoptosis. Various authors have also emphasized on Hsp90 as a key organizer in various pathways, as it binds to steroid receptors and to several serine and tyrosine kinases including the Src, Raf, focal adhesion kinases and protein kinase casein kinase II or cyclin-dependent kinases-4, -6 and -9. [10],[11],[12]

The production mechanism of HSPs involve a signaling pathway leading to the activation of transcription factors called heat shock transcription factors (HSFs), which in turn controls transcription of HSP genes. [13] Though there are multiple HSFs responsible for expression of HSPs that have been implicated in the malignant phenotype of human cancers, studies have reported HSF-1 to be the main regulator of the short-term induction of HSPs. In resting cells, HSF-1 is a monomer; however, in stressed cells, active HSF-1 acts as a trimer, which is capable of binding to the promoter site of the stress protein gene and initiating transcription and translation. [14]

According to Morimoto in 1991, HSPs expression is amplified in carcinomas during cell proliferation, differentiation and oncogenesis, in conditions that lead to DNA apoptosis, inducing regulation of apoptosis and modulation of immune response. Their role as molecular chaperones leads to interaction with large molecules and inactivate proliferation suppressors by direct disruption or by prevention of repressor binding to DNA target. [15] More than a decade later, review by other authors suggest the same role of HSPs in cancer mechanism. [6]

 Hsps And Hnscc

HNSCC like other tumors, their cells are also exposed to a variety of environmental stress, lack of oxygen supply and nutrients, etc., These cells acquire an aggressive phenotype and undergo changes to endure their capability to persist and proliferate. Existing literature emphasizes that in such hypoxic conditions, hypoxic inducible factor (HIF) initiates the expression of genes, causing changes in anaerobic metabolism, angiogenesis, invasion and survival [Figure 1]. [16],[17] HIF induced gene expression in turn plays an eminent role in the invasion and metastasis by regulating and increasing lysyl oxidase (which regulates the cell-matrix adhesion and invasion) and chemokine (C-X-C motif) receptor CXCR4, together with its ligand, the chemokine stromal-cell-derived factor 1 (SDF-1), also called CXC chemokine ligand 12 (CXCL12) to facilitate cancer cell survival. [18],[19],[20] This CXCR4-CXCL2 complex binds together to tumor cells at the primary metastatic site, facilitating secretion of angiogenic factors also. [4] {Figure 1}

In view of HSPs function in the development of HNSCC under hypoxic condition due to stress, several studies were carried out to implicate them either as a diagnostic or prognostic marker in HNSCC [Table 1]. [21],[22],[23],[24],[25],[26],[27] In recent times, another perception toward HSPs has started to emerge, i.e., to target HSPs/HSFs directly or by drugs. This concept seems like an exciting new access toward cancer therapy because HSPs are essential for cell survival during tumor progression and metastasis. As an example; Zhu et al., concluded that targeting and silencing Hsp27 may decrease metastasis in head and neck squamous cell cancer cells as Hsp27 has the potential to regulate metastasis of HNSCC cells. [28] The brand new trend is mostly about targeting Hsp90, as the authors argue that the purpose for existence of such a large amount of Hsp90 in cells by mother nature is for normal cells to initiate a rapid defensive response to environmental insults, including heat, hypoxia, ultraviolet rays, gamma-irradiation, reactive oxygen species (ROS), injury-released growth factors. [29] This hypothesis altogether provides a new perspective towards using Hsp90 for target therapy.{Table 1}

 Hsp90 and Its Utility In Hnscc

From a decade it's been relevant that Hsp90 contains at least two chaperone-sites, one in its N-terminal domain and another in the C-terminal domain suggests the presence of a large variety of active surfaces making it more available for binding sites by various factors. Hsp90 expression on the cell surface (extracellular heat shock protein 90 [eHsp90]) either as a tumor antigen or a protein that assists antigen presentation to antigen-presenting cell was reported in late 1970s. [11],[29],[30] Then a secreted version termed eHsp90α with functions to promote cell motility, a crucial event for both wound healing and cancer was characterized. Li et al. after intensive research identified a key upstream regulator of Hsp90α secretion, the HIF-1α in human dermal fibroblasts and keratinocytes. [31],[32] Cheng et al. in their investigations since 2004, reported that low density lipoprotein receptor-related protein 1/cluster of differentiation 91 (LRP-1/CD91) was a cell surface receptor for eHsp90α and its role was to promote cell migration and tumor invasion via signaling. [33] On this basis, further Tsutsumi et al. postulated the relation between hypoxic cells, eHsp90α and cell motility, which is a necessity for metastasis and tumor invasion [Figure 2]. [34] {Figure 2}

It has also been modulated that secretion of Hsp90α is an alternative strategy for cancer cells to bypass the anti-motility of TGF-β without mutating TGF-β signaling components. [35] Lately, the N-terminus of Hsp90 has been located as the cellular target of Novel triazine S06, a compound, which effectively reduced HNSCC invasion by inhibiting secretion of carcinoma-associated fibroblasts (CAFs)-derived proinvasive chemokines. They emphasized that targeting Hsp90 for stromal-based therapy to curb proinvasive molecular crosstalk within the tumor microenvironment would prove to be an attractive candidate for anti-cancer drug development in oral squamous cell carcinoma (OSCC). [36]


Due to lack of specificity and their wide expression in various conditions the HSPs are still not considered as the diagnostic biomarkers of choice. However, they can be used along with other tumor specific markers to help optimum therapeutic strategy. In addition, the increased expression of HSPs in tumors is forming the basis of chaperone-based immunotherapy. Clinical trials have shown notable results using of Hsp90 inhibitors, for example; the natural product geldanamycin (GM) or the GM analog 17AAG. [5] A vital tool for the future studies is to specifically target this Hsp90 and see its potential role as a diagnostic marker and develop inhibitors that can act as a therapeutic aid for OSCC patients. With the powerful approaches of both genetics and biochemistry, we hope that future research will unearth the full potential of Hsp90s in OSCC, as encouraging results have already been demonstrated in melanoma, acute myeloid leukemia, castration refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma.


1Hartl FU. Molecular chaperones in cellular protein folding. Nature 1996;381:571-9.
2Schlesinger MJ. Heat shock proteins. J Biol Chem 1990;265:12111-4.
3Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol 2009;45:301-8.
4Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143-54.
5Khalil AA, Kabapy NF, Deraz SF, Smith C. Heat shock proteins in oncology: Diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta 2011;1816:89-104.
6Ciocca DR, Calderwood SK. Heat shock proteins in cancer: Diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 2005;10:86-103.
7Arrigo AP. Small stress proteins: Chaperones that act as regulators of intracellular redox state and programmed cell death. Biol Chem 1998;379:19-26.
8Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S. Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. EMBO J 1999;18:2040-8.
9Gabai VL, Meriin AB, Mosser DD, Caron AW, Rits S, Shifrin VI, et al. Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J Biol Chem 1997;272:18033-7.
10Buchner J. Hsp90 and Co. A holding for folding. Trends Biochem Sci 1999;24:136-41.
11Csermely P, Schnaider T, Soti C, Prohászka Z, Nardai G. The 90-kDa molecular chaperone family: Structure, function, and clinical applications. A comprehensive review. Pharmacol Ther 1998;79:129-68.
12Miyata Y, Yahara I. The 90-kDa heat shock protein, HSP90, binds and protects casein kinase II from self-aggregation and enhances its kinase activity. J Biol Chem 1992;267:7042-7.
13Whitley D, Goldberg SP, Jordan WD. Heat shock proteins: A review of the molecular chaperones. J Vasc Surg 1999;29:748-51.
14Morimoto RI, Sarge KD, Abravaya K. Transcriptional regulation of heat shock genes. A paradigm for inducible genomic responses. J Biol Chem 1992;267:21987-90.
15Morimoto RI. Heat shock: The role of transient inducible responses in cell damage, transformation, and differentiation. Cancer Cells 1991;3:295-301.
16Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441:437-43.
17Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008;8:180-92.
18Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 2007;117:3810-20.
19Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006;440:1222-6.
20Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von hippel-lindau tumour suppressor pVHL. Nature 2003;425:307-11.
21Sugerman PB, Savage NW, Xu LJ, Walsh LJ, Seymour GJ. Heat shock protein expression in oral epithelial dysplasia and squamous cell carcinoma. Eur J Cancer PartB Oral Oncol 1995;31B: 63-7.
22Kaur J, Das SN, Srivastava A, Ralhan R. Cell surface expression of 70 kDa heat shock protein in human oral dysplasia and squamous cell carcinoma: Correlation with clinicopathological features. Oral Oncol 1998;34:93-8.
23Kaur J, Srivastava A, Ralhan R. Expression of 70-kDa heat shock protein in oral lesions: Marker of biological stress or pathogenicity. Oral Oncol 1998;34:496-501.
24Fan GK, Chen J, Ping F, Geng Y. Immunohistochemical analysis of P57(kip2), p53 and hsp60 expressions in premalignant and malignant oral tissues. Oral Oncol 2006;42:147-53.
25Suzuki H, Sugimura H, Hashimoto K. Overexpression of heat shock protein 27 is associated with good prognosis in the patient with oral squamous cell carcinoma. Br J Oral Maxillofac Surg 2007;45:123-9.
26Mohtasham N, Babakoohi S, Montaser-Kouhsari L, Memar B, Salehinejad J, Rahpeyma A, et al. The expression of heat shock proteins 27 and 105 in squamous cell carcinoma of the tongue and relationship with clinicopathological index. Med Oral Patol Oral Cir Bucal 2011;16:e730-5.
27Ishiwata J, Kasamatsu A, Sakuma K, Iyoda M, Yamatoji M, Usukura K, et al. State of heat shock factor 1 expression as a putative diagnostic marker for oral squamous cell carcinoma. Int J Oncol 2012;40:47-52.
28Zhu Z, Xu X, Yu Y, Graham M, Prince ME, Carey TE, et al. Silencing heat shock protein 27 decreases metastatic behavior of human head and neck squamous cell cancer cells in vitro. Mol Pharm 2010;7:1283-90.
29Cheng CF, Fan J, Zhao Z, Woodley DW, Li W. Secreted heat shock protein-90alpha: A more effective and safer target for anti-cancer drugs? Curr Signal Transduct Ther 2010;5:121-7.
30Tsutsumi S, Neckers L. Extracellular heat shock protein 90: A role for a molecular chaperone in cell motility and cancer metastasis. Cancer Sci 2007;98:1536-9.
31Li W, Li Y, Guan S, Fan J, Cheng CF, Bright AM, et al. Extracellular heat shock protein-90alpha: Linking hypoxia to skin cell motility and wound healing. EMBO J 2007;26:1221-33.
32Woodley DT, Fan J, Cheng CF, Li Y, Chen M, Bu G, et al. Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90alpha autocrine signaling to promote keratinocyte migration. J Cell Sci 2009;122:1495-8.
33Cheng CF, Fan J, Fedesco M, Guan S, Li Y, Bandyopadhyay B, et al. Transforming growth factor alpha (TGFalpha)-stimulated secretion of HSP90alpha: Using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-rich environment during wound healing. Mol Cell Biol 2008;28:3344-58.
34Tsutsumi S, Mollapour M, Graf C, Lee CT, Scroggins BT, Xu W, et al. Hsp90 charged-linker truncation reverses the functional consequences of weakened hydrophobic contacts in the N domain. Nat Struct Mol Biol 2009;16:1141-7.
35Li W, Sahu D, Tsen F. Secreted heat shock protein-90 (Hsp90) in wound healing and cancer. Biochim Biophys Acta 2012;1823:730-41.
36Jung DW, Kim J, Che ZM, Oh ES, Kim G, Eom SH, et al. A triazine compound S06 inhibits proinvasive crosstalk between carcinoma cells and stromal fibroblasts via binding to heat shock protein 90. Chem Biol 2011;18:1581-90.