Abstract
Chemotherapy and anti-hormonal therapies are the most common treatments for non-organ-confined prostate cancer (PCa). However, the effectiveness of these therapies is limited, thus necessitating the development of alternative approaches. The present study focused on analyzing the role of pterostilbene (PTER)-isothiocyanate (ITC) conjugate – a novel class of hybrid compound synthesized by appending an ITC moiety on PTER backbone – in regulating the functions of androgen receptor (AR), thereby causing apoptosis of PCa cells. The conjugate molecule caused 50% growth inhibition (IC50) at 40±1.12 and 45±1.50 μM in AR positive (LNCaP) and negative (PC-3) cells, respectively. The reduced proliferation of PC-3 as well as LNCaP cells by conjugate correlated with accumulation of cells in G2/M phase and induction of caspase dependent apoptosis. Both PI3K/Akt and MAPK/ERK pathways played an important and differential role in conjugate-induced apoptosis of these PCa cells. While the inhibitor of Akt (A6730) or Akt-specific small interference RNA (siRNA) greatly sensitized PC-3 cells to conjugate-induced apoptosis, on the contrary, apoptosis was accelerated by inhibition of ERK (by PD98059 or ERK siRNA) in case of LNCaP cells, both ultimately culminating in the expression of cleaved caspase-3 protein. Moreover, anti-androgenic activity of the conjugate was mediated by decreased expression of AR and its co-activators (SRC-1, GRIP-1), thus interfering in their interactions with AR. All these data suggests that conjugate-induced inhibition of cell proliferation and induction of apoptosis are partly mediated by the down regulation of AR, Akt, and ERK signaling. These observations provide a rationale for devising novel therapeutic approaches for treating PCa by using conjugate alone or in combination with other therapeutics.
Highlights
Despite significant efforts made towards the ablation of cancers, prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death among men in the United States, with an estimated 217,730 new cases and 32,050 deaths in 2010 [1]
Pifithrin-a (p53 inhibitor), antibodies for caspase-3, Bax, Akt, p-Akt, extracellular-regulated kinase (ERK), p-ERK, SRC-1, GRIP-1, N-CoR, b-actin and small interfering RNAs against Akt, ERK and control were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA)
Our data showed that the treatment of LNCaP and PC-3 PCa cells with RESV, PTER and conjugate resulted in a dose dependent inhibition of cell proliferation
Summary
Despite significant efforts made towards the ablation of cancers, prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death among men in the United States, with an estimated 217,730 new cases and 32,050 deaths in 2010 [1]. Up regulation of epidermal growth factor receptor (EGFR) and subsequent increases in extracellular-regulated kinase (ERK) and Akt signaling, are implicated in PCa progression [9]. An earlier study showed that inhibition of Akt pathway abrogates the HER2/neu-induced AR signaling activity [10]. These results suggest that Akt is an activator of AR required for androgen-independent survival and growth of PCa cells. Research has shown that inhibition of one or both of these pathways has a more profound effect on tumor cell development and death, making them attractive combinational targets in PCa therapy. AR, Akt, and ERK could be potential targets for the treatment of PCa
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