Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer

Abstract

Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate cancer (PCa). Although the members of the STAT protein family are structurally similar, they convey different functions in PCa. STAT1, STAT3, and STAT5 are associated with therapy resistance. STAT1 and STAT3 are involved in docetaxel resistance, while STAT3 and STAT5 are involved in antiandrogen resistance. Expression of STAT3 and STAT5 is increased in PCa metastases, and together with STAT6, they play a crucial role in PCa metastasis. Further, expression of STAT3, STAT5, and STAT6 was elevated in advanced and high-grade PCa. STAT2 and STAT4 are currently less researched in PCa. Since STATs are widely involved in PCa, they serve as potential therapeutic targets. Several inhibitors interfering with STATs signaling have been tested unsuccessfully in PCa clinical trials. This review focuses on the respective roles of the STAT family members in PCa, especially in metastatic disease and provides an overview of STAT-inhibitors evaluated in clinical trials.

Influence of Systemic Therapy on the Expression and Activity of Selected STAT Proteins in Prostate Cancer Tissue

“…STAT proteins influence multiple biological processes such as immune response, mitogenesis, wound healing, cell survival, and cell growth [5,23]. After activation, the transcription factors transmit their signals from the cell membrane through growth factors, cytokines, or hormones into the nucleus.…”

“…STAT protein expression was reported to change during malignant transformation of the prostate [5]. Therefore, to evaluate STAT3 (Figure 2), 5 (Figure 3) and 6 protein expression (Figure 4) patterns in BPH and PCa, tissue of the presented patient cohort was investigated using the Remmele Score.…”

“…Systemic therapy such as ADT, NHT, or CTx was reported to change STAT expression and activity and promote tumor progression and therapy resistance [5,10,12,16,17,22]. Therefore, the ADT PCa cohort was divided into HSPC and ADT subgroups to verify these findings.…”

“…The PARP-inhibitor Olaparib was recently approved for patients with mCRPC and alteration of one or more homologous recombination repair genes [4]. Unfortunately, despite recent improvements in treatment options, patients suffering from mCRPC only have a median life expectancy of 19 months due to tumor progress and emerging therapy resistance [5].…”

“…The Signal Transducers and Activators of Transcription (STATs) are a group of transcription factors, which reportedly are involved in those life-threatening processes in PCa [5]. The group contains seven members, of which STAT3, STAT5, and STAT6 are involved in tumor progress, metastasis, and therapy resistance.…”