Simultaneous Inhibition of SRC and STAT3 Induces an Apoptotic Response in Prostate Cancer Cells

Abstract

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and the second leading cause of cancer-related deaths in American men. Recent studies have suggested that sarcoma inducing kinase (SRC) and its downstream signaling targets are implicated in prostate cancer, but the mechanisms behind how SRC inhibition induces apoptosis are still poorly understood. This study focused specifically on the interactions between SRC and its one of its downstream targets, Signal transducer and activator of transcription 3 (STAT3), in prostate cancer cells. Contrary to studies on the SRC/STAT3 pathway, western blotting showed that SRC inhibition had minimal effects on phosphorlyated-STAT3 levels in DU145 prostate cancer cells. Simultaneous inhibition of both SRC and STAT3 through PP2 (inhibits SRC expression) and STAT3 siRNA, respectively, led to more distinct poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, a hallmark indicator of apoptosis. qRT-PCR analysis showed a two-fold and three-fold decrease between simultaneous versus exclusive treatments in levels of induced myeloid cell leukemia (MCL-1), a pro-survival gene. Together, these findings suggest that the inhibition of STAT3 through SRC is ineffective and that the independent inhibition of STAT3 induces a stronger apoptotic response. Additionally, the study suggests that the simultaneous inhibition of SRC and STAT3 may be a novel and promising treatment for prostate cancer.