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Adetola L. Shodeinde
Pharmacology & Physiology Program
B.S., 2004, Tuskegee University, Alabama

Thesis Advisor: Beverly E. Barton, Ph.D.
Adjunct Associate Professor
Department of Surgery

Tuesday, April 16, 2013
12:30 P.M., MSB Room H-609


In 2013, prostate cancer will once again be the second leading cause of cancer death of American males. Although initially treatable, prostate cancer can recur in a hormone refractory form that is non-responsive to current available therapies. The mortality rates associated with hormone refractory prostate cancer is high. There is an urgent need for new therapeutic agents to treat prostate cancer. In recent years, inhibitors of signal transducer and activator of transcription 3 (STAT3) have emerged as promising molecular candidates for targeted prostate cancer therapy. A common feature of prostate cancer is the dependence on constitutively activated STAT3, a transcription factor, for survival. More importantly, inhibition of STAT3 has been shown to induce apoptosis in prostate cancer cells. Persistent aberrant activation of STAT3 is thought to be mediated by homodimers of phosphorylated STAT3, which translocate to the nucleus. STAT3 has also been observed to heterodimerize with STAT1 and STAT2. However, the contributions of STAT3:STAT1 and STAT3:STAT2 heterodimers to the survival of malignant cells have not been examined in detail.

Previously we reported that novel single-stranded oligonucleotides created in the laboratory (containing consensus STAT3 binding sequences) were more effective in inducing apoptosis in prostate cancer cells than antisense STAT3 oligonucleotides. Control scrambled-sequence oligonucleotides had no effect. To ensure that these novel anti-STAT3 oligonucleotides were indeed STAT3 specific, we decided to investigate what role STAT1 and STAT2, if any, played in the maintenance of STAT3 dependent cells (meaning disruption of expression of STAT3 in these cells induces apoptosis). Here we report that these novel anti-STAT3 oligonucleotides induced apoptosis in STAT1-null and STAT2-null fibrosarcoma cell lines U3A and U6A, as well as in the parental fibrosarcoma cell line 2fTGH. Forty-eight hours after transfection of novel anti-STAT3 oligonucleotides, significant apoptosis was observed in 2fTGH, U3A, and U6A cells. The cell lines expressed constitutively-activated STAT3 and depended on its activity for survival. Scrambled-sequence oligonucleotides had no effect on survival. These data indicate that neither STAT1 nor STAT2 play significant roles in the maintenance of these cells and that our novel anti-STAT3 oligonucleotides are indeed STAT3 specific.

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