Abstract
Despite of tremendous research efforts to profile prostate cancer, the genetic alterations and biological processes that correlate with disease progression remain partially elusive. In this study we show that the STAT3 small molecule inhibitor Stattic caused S-phase accumulation at low-dose levels and led to massive apoptosis at a relatively high-dose level in prostate cancer cells. STAT3 knockdown led to the disruption of the microvascular niche which tumor-initiating cells (TICs) and non-tumor initiating cells (non-TICs)depend on. Primary human prostate cancer cells and prostate cancer cell line contained high aldehyde dehydrogenase activity (ALDH(high)) subpopulations with stem cell-like characteristics, which expressed higher levels of the active phosphorylated form of STAT3 (pSTAT3) than that of non-ALDH(high) subpopulations. Stattic could singnificantly decrease the population of ALDH(high) prostate cancer cells even at low-dose levels. IL-6 can convert non-ALDH(high) cells to ALDH(high) cells in prostate cancer cell line as well as from cells derived from human prostate tumors, the conversion mediated by IL-6 was abrogated in the presence of STAT3 inhibitor or upon STAT3 knockdown. STAT3 knockdown significantly impaired the ability of prostate cancer cells to initiate development of prostate adenocarcinoma. Moreover, blockade of STAT3 signaling was significantly effective in eradicating the tumor-initiating and bulk tumor cancer cell populations in both prostate cancer cell-line xenograft model and patient-derived tumor xenograft (PDTX) models. This data suggests that targeting both tumor initiating and differentiated cell populations by STAT3 inhibition is predicted to have greater efficacy for prostate cancer treatment.
Highlights
Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer related deaths in men worldwide [1]
Our results showed that Stattic effectively eliminated the ALDHhigh subpopulation in PC3M-1E8 cells and primary cell cultures from different clinical prostate cancer samples, even at a low doses (Fig. 3E), suggesting that this subpopulation of prostate Tumor-initiating cells (TICs) is sensitive to Signal Transducer and Activator of Transcription 3 (STAT3)-mediated inhibition
Using the STAT3 small molecule inhibitor, Stattic, which has been shown to selectively inhibit the function of the STAT3 SH2 domain regardless of STAT3 phosphorylation status [30], we showed that Stattic potentially prevented phosphorylation of STAT3 in prostate cancer cells
Summary
Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer related deaths in men worldwide [1]. High ALDH activity has successfully been used to identify tumor-initiating and metastasisinitiating cells in human prostate cancer [8]. STAT3 plays an important role in maintaining pluripotency and selfrenewing processes in embryonic stem cells [14, 15] In these cells, activation of the STAT3 protein is a reversible, tightly controlled process that typically lasts for a limited duration [16]. Active STAT3 contributes to oncogenesis by preventing apoptosis, inducing cell proliferation and suppressing anti-tumor immune responses [16]. These make STAT3 an excellent molecular candidate for cancer therapy. We investigated the role of activated STAT3 signaling on differentiated cancer cell and TIC development in prostate cancer. Our findings provide new mechanistic insights for prostate cancer development
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