Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells

Abstract

BACKGROUND New therapies are required for castrate‐resistant prostate cancer (CRPC), and growth‐arrest specific 5 (GAS5) lncRNA, which riborepresses androgen receptor action, may offer novel opportunities in this regard. This lncRNA promotes the apoptosis of prostate cancer cells and its levels decline as prostate cancer cells acquire castrate‐resistance, so that enhancing GAS5 expression may improve the effectiveness of chemotherapies. Since GAS5 is a member of the 5' terminal oligopyrimidine gene family, we have examined mTOR inhibition as a strategy to increase GAS5 expression. Furthermore, we have determined if GAS5 itself mediates the action of mTOR inhibitors, as demonstrated for other chemotherapeutic agents in prostate cancer cells. METHODS The effects of mTOR inhibitors on GAS5 lncRNA levels and cell growth were determined in a range of prostate cancer cell lines. Transfection of cells with GAS5 siRNAs and plasmid constructs was performed to determine the involvement of GAS5 lncRNA in mTOR inhibitor action. RESULTS First generation mTORC1, combined mTORC1/mTORC2 and dual PI3K/mTOR inhibitors all increased cellular GAS5 levels and inhibited culture growth in androgen‐dependent (LNCaP) and androgen‐sensitive (22Rv1) cell lines, but not in androgen‐independent (PC‐3 and DU 145) cell lines. The latter exhibited low endogenous GAS5 expression, and GAS5 silencing in LNCaP and 22Rv1 cells decreased the sensitivity to mTOR inhibitors, whereas transfection of GAS5 lncRNA sensitized PC‐3 and DU 145 cells to these agents. CONCLUSION mTOR inhibition enhances GAS5 transcript levels in certain prostate cancer cell lines. This selectivity is likely to be related to endogenous GAS5 expression levels, since GAS5 lncRNA is itself required for mTOR inhibitor action in prostate cancer cells. Prostate 75:693–705, 2015. © 2015 Wiley Periodicals, Inc.

Long non-coding RNA GAS5 inhibits cell proliferation, induces G0/G1 arrest and apoptosis, and functions as a prognostic marker in colorectal cancer

“…GAS5 was initially identified during screening for potential tumor suppressor genes (29) and is a stress-inducible gene, which is differentially expressed in healthy and tumor tissues/cell lines (30). In addition, GAS5 has been demonstrated to be involved in the regulation of the cell cycle (31) and to function as a tumor suppressor in human T cells, and breast and prostate cancer cell lines by inducing apoptosis (10,11,32,33). Furthermore, reduced expression of GAS5 and/or its snoRNAs has been observed in head and neck squamous cell carcinomas, and gastric and cervical cancer (34)(35)(36), indicating that it serves an important role in tumorigenesis.…”

Knockdown of Long Non-Coding RNA GAS5 Increases miR-23a by Targeting ATG3 Involved in Autophagy and Cell Viability

“…Accumulating evidences demonstrated that lncRNA growth arrest-specific 5 (GAS5) acted as a powerful regulator of various biological activities, including tumor metastasis [29], vascular remodeling [30], autoimmune and inflammatory diseases [31]. Recently, GAS5 has been reported to involve in autophagy in NSCLC cells [32], and negatively correlated with mTOR [33,34], which is a crucial regulator of autophagy [35]. Although GAS5 has been suggested to mediate autophagy program, the underlying mechanism still remains to be further confirmed.…”

Long Non-coding RNA Growth Arrest-specific Transcript 5 (GAS5) Inhibits Liver Fibrogenesis through a Mechanism of Competing Endogenous RNA

“…It is therefore a therapeutic target for gastric cancer and has been proposed as a potential biomarker for poor prognosis (19). GAS5 has also been shown to promote the apoptosis of prostate cancer cells, and decreased expression of GAS5 may lower the effectiveness of chemotherapeutic drugs in prostate cancer patients (20,21). GAS5 expression is both essential and sufficient for normal growth arrest in T cell lines and human peripheral blood T cells (22).…”