The transcription factor, heat shock factor 1 (HSF1), influences the expression of heat shock proteins as well as other activities like the induction of tumor suppressor genes, signal transduction pathway, and glucose metabolism.
In addition, HSF1 overexpression was significantly associated with some phenotypes of tumor aggressiveness including TNM stage, histological grade, lymph node metastasis, and vascular invasion.
Pharmacologic inhibition induced tumor growth inhibition and was well-tolerated in a human myeloma xenograft murine model with evidence of pharmacodynamic biomarker modulation.<b>Conclusions:</b> Taken together, our studies demonstrate the dependence of myeloma cells on HSF1 for survival and support the clinical evaluation of pharmacologic inhibitors of the HSF1 pathway in myeloma.<i>Clin Cancer Res; 24(10); 2395-407.
Using an orthotopic xenograft mouse model, we found that combined targeting of AKT and HSF1 to significantly reduce tumor growth, induce tumor apoptosis, delay time to metastasis, and prolong host survival.
In the present study, it was investigated whether small interfering (si)RNA against PLK1 or HSF1 could suppress tumor growth <i>in vitro</i> and <i>in vivo</i>.
XAF1 is a pro-apoptotic protein and its restoration was found to sensitize cancer cells to apoptotic stimuli; however, the precise mechanism involved in the downregulation of XAF1 in tumors is unknown and promoter hypermethylation or heat-shock transcription factor 1 (HSF1) may be involved.
Univariate and multivariate analyses demonstrated that 216 patients (52%) with tumour expressing three or four markers in a panel of HSP60, HSP70, HSP90 and HSF1 had a significantly heightened risk for cancer-specific mortality than tumours expressing fewer than three markers (P < 0.0001; concordance index, 0.81).
HSP90 was downregulated by TCCP by inactivation of HSF-1 resulting in inhibition of tumor cell proliferation, VEGF-induced cell migration, and concomitant decrease in tumor burden and neo-angiogenesis in vivo.
To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6 , heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn.
Inhibition of heat shock protein 90 (Hsp90) is known to induce the heat shock response via activation of HSF1 which is associated with tumor development, metastasis and therapy resistance and also with an increased susceptibility to NK cell-mediated lysis.
In conclusion, our study indicates that one of the potential HSP-independent HSF1 driven mechanisms that may contribute to poor outcome in human tumors involves regulation of the CSC phenotype.
Knockdown of HSF1 with shRNA induced the protein expression of tumor suppressor retinoblastoma protein, resulting in attenuated plc/prf5 cell growth and colony formation in vitro.
HSF1 could be also activated by altered kinase signaling characteristic for cancer cells, which is a probable reason for its high activity found in a broad range of tumors.
A striking combinational effect was observed when HSF1 knockdown plus with HSP90 inhibitors treatment in various cancer cell lines and tumor mouse models.
Several pharmacological inhibitors of PKC have been demonstrated to exert inhibitory effects on the activation of HSF1 and, therefore, induce apoptosis in tumor cells.
Thus, cancers of many histologies exhibit activated HSF1 and increased HSP levels that may help to deter tumor suppression and evade therapy in the clinic.