Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer

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 (ALDHhigh) subpopulations with stem cell-like characteristics, which expressed higher levels of the active phosphorylated form of STAT3 (pSTAT3) than that of non-ALDHhigh subpopulations. Stattic could singnificantly decreas the population of ALDHhigh prostate cancer cells even at low-dose levels. IL-6 can convert non-ALDHhigh cells to ALDHhigh 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.

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…Here, our data show that in the absence of SOCS1, STAT3, but not STAT1, is highly activated via phosphorylation. Further, treatment of mice with a STAT3 blocking peptide, STATTIC (39,64,65), reduces both mortality and bacterial burden in iKIR-treated septic mice. STAT3 is activated by IL-6 (66).…”

STAT3 down‐regulation induces mitochondria‐dependent G2/M cell cycle arrest and apoptosis in oesophageal carcinoma cells

“…However, the mechanisms of oesophageal cancer growth and metastasis are not fully understood, which impedes the development of effective treatments. Studies have demonstrated the STAT3 signalling pathway plays a key role in carcinogenesis by promoting cancer proliferation and inhibition of apoptosis . STAT3 exists in a latent form in the cytoplasm but is activated by a wide variety of cell surface receptors via tyrosine phosphorylation to form dimers and translocate into the nucleus, where it binds to STAT‐specific DNA response elements on the promoters of a number of oncogenes such as cyclin B1, c‐Myc, Bcl‐2, P53 .…”

The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation

“…Phosphorylated STAT3 dimerizes and translocates into the nucleus to bind to specific DNA response elements to induce the transcription of downstream genes, such as BCL-xL, MCL1 and c-Myc (32). Targeting STAT3 signaling results in suppression of the proliferation of various cancer cells in vitro and tumorigenicity in vivo (33,34). Therefore, the identification and development of novel drugs targeting deregulated STAT3 activation effectively remains an important scientific and clinical challenge (35,36).…”