Abstract
Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer.
Highlights
Prostate cancer is the second most common diagnosed cancer in men worldwide and the first in developed countries
Since GL inhibits both STAT3 and NF-κB transcriptional activities, and both transcription factors participated in the progression of cell cycle in cancer cells [6, 38, 39], we were interested in studying the effect of GL on the cell cycle of prostate cancer cells
STAT3 and NF-κB have been identified to be involved in the processes of cell proliferation, cell differentiation and cell survival and, play an important role in tumorigenesis
Summary
Prostate cancer is the second most common diagnosed cancer in men worldwide and the first in developed countries. 18-24 months later, the majority of patients does not respond to ADT and develop a castration-resistant prostate cancer (CRPC), which is associated with a poor prognosis, and mean survival [2,3,4,5]. STAT3 belongs to the signal transducers and activators of transcription (STATs) family of transcription factors. STAT3 is activated in response to several growth factors and cytokines and is involved in numerous physiological processes such as inflammation, cell growth and differentiation. Constitutive activation of STAT3 has been observed in many tumor types, including prostate cancer [6,7,8,9]. STAT3 regulates the expression of cell-cycle regulators, angiogenic factors and anti-apoptotic genes, promoting tumorigenesis [10]
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