Novel role of Stat1 in the development of docetaxel resistance in prostate tumor cells

Abstract

A major obstacle for clinicians in the treatment of advanced prostate cancer is the inevitable progression to chemoresistance, especially to docetaxel. It is essential to understand the molecular events that lead to docetaxel resistance in order to identify means to prevent or interfere with chemoresistance. In initial attempts to detect these events, we analysed genomic differences between non-resistant and docetaxel-resistant prostate tumor cells and, of the genes modulated by docetaxel treatment, we observed Stat1 and clusterin gene expression heightened in the resistant phenotype. In this study, we provide biochemical and biological evidence that these two gene products are related. Stat1 and clusterin protein expression was induced upon docetaxel treatment of DU145 cells and highly overexpressed in the docetaxelresistant DU145 cells (DU145-DR). The increase in total Stat1 corresponded to an increase in phosphorylated Stat1. Interestingly, there was no detectable difference between DU145 and DU145-DR cells expression of total Stat3 and phosphorylated Stat3. Treatment of DU145-DR cells with small interfering RNA targeted for Stat1 not only resulted in the knockdown of Stat1 expression, but it also caused the inhibition of clusterin expression. Thus, Stat1 appears to play a key role in the regulation of clusterin. Remarkably, inhibition of Stat1 or clusterin expression resulted in the re-sensitization of DU145-DR cells to docetaxel. These results offer the first evidence that Stat1, and its subsequent regulation of clusterin, are essential for docetaxel resistance in prostate cancer. Targeting this pathway could be a potential therapeutic means for intervention of docetaxel resistance.

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

“…On another avenue, the STAT and JAKs pathways have already shown to be involved in PC-3 cell growth through IL-6 and NFkB protein stimulation [47]. STAT1a also plays a role in the development of docetaxel resistance in prostate cancer tumor cells [52]. Another gene regulated by the androgen receptor in LNCaP cells is the ATP-binding cassette transporter A1 (ABCA1).…”

A novel defense mechanism that is activated on amyloid-β insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling

“…25 In addition, increase in STAT1 and STAT1 phosphorylation plays a role in docetaxol resistance in prostate tumor cells through regulation of clusterin. 26 To further elucidate the role of STAT1 involved in apoptosis, in this study we examined whether Ab activates STAT1 and whether STAT1 activation by Ab mediates apoptosis or survival. We also examined the expression of the anti-apoptotic gene Mcl-1 27,28 involved in Ab toxicity.…”

Single cell phospho‐specific flow cytometry can detect dynamic changes of phospho‐Stat1 level in lung cancer cells

“…In prostate tumor cells, Stat1 expression is heightened in docetaxel-resistant cancer cells (17). Transfection of Stat1-specific siRNA into docetaxelresistant cells results in re-sensitization to docetaxel.…”

“…The clinico-pathologic characteristics of Patients A and B were listed in Table 1 Different Patterns of Stat1 Activation in Cancer Cells from MPE had Different Sensitivities to Cisplatin Cisplatin was the main agent for treating advanced lung cancer (10). Because Stat1 activation might contribute to drug resistance of cancer cells (16,17), the relationship between Stat1 activation after IFN-c stimulation and cell sensitivity to cisplatin in cancer cells from MPEs was investigated. Cancer cells from MPEs of another six lung cancer patients were analyzed (Table 1, Patients 1-6).…”