STAT3 inhibition induces apoptosis in cancer cells independent of STAT1 or STAT2

Adetola Shodeinde; Kalyani Ginjupalli; H. Dan Lewis; Sheraz Riaz; Beverly E Barton

STAT3 inhibition induces apoptosis in cancer cells independent of STAT1 or STAT2

Adetola Shodeinde, Kalyani Ginjupalli, H. Dan Lewis, Sheraz Riaz, Beverly E Barton

Abstract

Signal transducers and activators of transcription (STATs) were originally discovered as mediators of signal transduction. Persistent aberrant activation of STAT3 is part of the malignant phenotype of hormone-refractory prostate cancer and pancreatic cancer; this is thought to be mediated by homodimers of phosphorylated STAT3, which translocate to the nucleus. One consequence of persistently-activated STAT3 in malignant cells is that they depend upon it for survival. STAT3 is 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 investigated in detail.

Previously we reported that single-stranded oligonucleotides containing consensus STAT3 binding sequences (13410 and 13411) were more effective for inducing apoptosis in prostate cancer cells than antisense STAT3 oligonucleotides. Control oligonucleotides (scrambled sequences) had no effect. STAT3-inhibiting oligonucleotide 13410, but not scrambled-sequence oligonucleotides, induced apoptosis in pancreatic cancer cells as well. Here we report that 13410 and derivative olignucleotides induced apoptosis in STAT1-null and STAT2-null fibrosarcoma cell lines U3A and U6A, as well as in the parental fibrosarcoma cell line 2fTGH. The cell lines expressed constitutively-activated STAT3 and depended on its activity for survival. Forty-eight hr after transfection of 13410 or related oligonucleotides, significant apoptosis was observed in 2fTGH, U3A and U6A cells. 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 by extension that STAT3:STAT1 and STAT3:STAT2 heterodimers regulate a different set of genes from STAT3:STAT3 homodimers.

Keywords

STAT1; STAT2; STAT3; prostate cancer; pancreatic cancer; inhibitors

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