Abstract
Despite many advances in oncology, almost all patients with pancreatic cancer (PC) die of the disease. Molecularly targeted agents are offering hope for their potential role in helping translate the improved activity of combination chemotherapy into improved survival. Heat shock protein 27 (Hsp27) is a chaperone implicated in several pathological processes such as cancer. Further, Hsp27 expression becomes highly upregulated in cancer cells after chemotherapy. Recently, a modified antisense oligonucleotide that is complementary to Hsp27 (OGX-427) has been developed, which inhibits Hsp27 expression and enhances drug efficacy in cancer xenograft models. Phase II clinical trials using OGX-427 in different cancers like breast, ovarian, bladder, prostate and lung are in progress in the United States and Canada. In this study, we demonstrate using TMA of 181 patients that Hsp27 expression and phosphorylation levels increase in moderately differentiated tumors to become uniformly highly expressed in metastatic samples. Using MiaPaCa-2 cells grown both in vitro and xenografted in mice, we demonstrate that OGX-427 inhibits proliferation, induces apoptosis and also enhances gemcitabine chemosensitivity via a mechanism involving the eukaryotic translation initiation factor 4E. Collectively, these findings suggest that the combination of Hsp27 knockdown with OGX-427 and chemotherapeutic agents such as gemcitabine can be a novel strategy to inhibit the progression of pancreas cancer.
Highlights
Heat shock protein 27 (Hsp27) seems to have a crucial role in regulating the balance between cell death and survival
To study the role of Hsp[27] in Pancreatic cancer (PC), we determine its expression level by immunostaining in 181 pancreas cancer specimens spotted on a tissue microarray (TMA)
While Hsp[27] staining was absent or weak in less aggressive tumors like intraductal papillary mucinous neoplasms of the pancreas (IPMNP) and endocrine pancreas tumors (EPT), it strongly increased with the loss of differentiation in pancreas adenocarcinomas (ADK)
Summary
Heat shock protein 27 (Hsp27) seems to have a crucial role in regulating the balance between cell death and survival. Hsp[27] is phosphoactivated during cell stress to form oligomers that prevent aggregation and/or regulate activity and degradation of certain client proteins.[7] Hsp[27] expression is increased in a variety of malignancies including prostate[8,9] breast,[10] gastric,[11] ovarian,[12] bladder[13] and pancreas cancer.[14] Hsp[27] overexpression has been associated with multi-drug resistance in several cancers[15] like prostate,[9] breast[16] and bladder.[17] Recently, Mori-Iwamoto et al.[18] demonstrated that Hsp[27] is a biomarker of PC cell’s resistance to gemcitabine and its downregulation mediated by interferon-gamma helps in cytotoxic effect of gemcitabine.[19]. Hsp[27] (OGX-427) is currently tested in phase II clinical trials for prostate, bladder, ovarian, breast and lung cancers in the United States and Canada.[21]
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