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Articles by E. R Hahm
Total Records ( 3 ) for E. R Hahm
  E. R Hahm and S. V. Singh
 

d,l-Sulforaphane (SFN), a synthetic analogue of broccoli-derived l-isomer, inhibits viability of human prostate cancer cells and prevents development of prostate cancer and distant site metastasis in a transgenic mouse model. However, the mechanism underlying the anticancer effect of SFN is not fully understood. We now show that SFN inhibits constitutive and interleukin-6 (IL-6)–inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer. Growth-suppressive concentrations of SFN (20 and 40 µmol/L) decreased constitutive (DU145 cells) and IL-6–induced (DU145 and LNCaP cells) phosphorylation of STAT3 (Tyr705) as well as its upstream regulator Janus-activated kinase 2 (Tyr1007/1008). Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL-6–induced transcriptional activity of STAT3 as judged by luciferase reporter assay and (b) nuclear translocation of phospho-STAT3 as revealed by immunofluorescence microscopy. Levels of many STAT3-regulated gene products, including Bcl-2, cyclin D1, and survivin, were also reduced in SFN-treated cells. The IL-6–mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis as evidenced by cytoplasmic histone-associated DNA fragmentation and cleavage of poly(ADP-ribose) polymerase and procaspase-3. Furthermore, knockdown of STAT3 protein using small interfering RNA resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation in DU145 cells. Suppression of STAT3 activation was also observed in cells treated with naturally occurring analogues of SFN. In conclusion, the present study indicates that inhibition of STAT3 partially contributes to the proapoptotic effect of SFN. Cancer Prev Res; 3(4); 484–94. ©2010 AACR.

  R. J Leeman Neill , S. E Wheeler , S. V Singh , S. M Thomas , R. R Seethala , D. B Neill , M. C Panahandeh , E. R Hahm , S. C Joyce , M Sen , Q Cai , M. L Freilino , C Li , D. E Johnson and J. R. Grandis
 

Treatment of human head and neck squamous cell carcinoma (HNSCC) cell lines with guggulsterone, a widely available, well-tolerated nutraceutical, demonstrated dose-dependent decreases in cell viability with EC50s ranging from 5 to 8 µM. Guggulsterone induced apoptosis and cell cycle arrest, inhibited invasion and enhanced the efficacy of erlotinib, cetuximab and cisplatin in HNSCC cell lines. Guggulsterone induced decreased expression of both phosphotyrosine and total signal transducer and activator of transcription (STAT)-3, which contributed to guggulsterone's growth inhibitory effect. Hypoxia-inducible factor (HIF)-1 was also decreased in response to guggulsterone treatment. In a xenograft model of HNSCC, guggulsterone treatment resulted in increased apoptosis and decreased expression of STAT3. In vivo treatment with a guggulsterone-containing natural product, Guggulipid, resulted in decreased rates of tumor growth and enhancement of cetuximab's activity. Our results suggest that guggulsterone-mediated inhibition of STAT3 and HIF-1 provide a biologic rationale for further clinical investigation of this compound in the treatment of HNSCC.

  J Lee , E. R Hahm and S. V. Singh
 

We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of human breast cancer cells in culture and in vivo in association with apoptosis induction. The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies including breast cancer. The WA treatment (2 and 4 µM) decreased constitutive (MDA-MB-231) and/or IL-6-inducible (MDA-MB-231 and MCF-7) phosphorylation of STAT3 (Tyr705) and its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008) in MDA-MB-231, which was accompanied by suppression of their protein levels especially at the higher concentration. Exposure of MDA-MB-231 or MCF-7 cells to WA also resulted in suppression of (i) transcriptional activity of STAT3 with or without IL-6 stimulation in both cells; (ii) dimerization of STAT3 (MDA-MB-231) and (iii) nuclear translocation of Tyr705-phosphorylated STAT3 in both cells. To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred a modest protection against WA-mediated suppression of MDA-MB-231 cell invasion. General implication of these findings is that WA can trigger apoptosis and largely inhibit cell migration/invasion of breast cancer cells even after IL-6-induced activation of STAT3, which should be viewed as a therapeutic advantage for this agent.

 
 
 
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