STAT3 as a Target of Natural Products in Cancer Therapy

Abstract

This thesis will discuss the role of signal transducer and activator of transcription 3 (STAT3), as an anti-cancer drug target. Additionally, this thesis will describe how STAT3 regulates cellular processes related to cancer, including; proliferation, survival, angiogenesis, evasion from the immune system, and tumor progression. In addition to describing the process by which STAT3 regulates these cancer-related cellular processes, the thesis will address some of the difficulties associated with attempting to inhibit STAT3 itself, due to the fact that STAT3 has numerous regulatory mechanisms that are dependent on its structure, along with multiple physiologic functions. Furthermore, the thesis provides special consideration for natural substances as multi-kinase modulators of STAT3-related signaling cascades, where curcumin and chelidonine serve as representative examples. As part of the discussion of chelidonine's mechanism(s) of action, it was noted that chelidonine represents a class of agents known as "context-dependent" modulators that can regulate the phosphorylation status of specific residues within STAT3 (Tyr705 and/or Ser727) under conditions dependent upon the cell-cycle state. Ultimately, the thesis supports the idea that natural products may utilize indirect or complex methods to regulate STAT3 signaling rather than functioning as direct STAT3 inhibitors.