Abstract
D, L-Sulforaphane (SFN), a synthetic racemic analog of broccoli constituent L-sulforaphane, is a highly promising cancer chemopreventive agent with in vivo efficacy against chemically-induced as well as oncogene-driven cancer in preclinical rodent models. Cancer chemopreventive effect of SFN is characterized by G2/M phase cell cycle arrest, apoptosis induction, and inhibition of cell migration and invasion. Moreover, SFN inhibits multiple oncogenic signaling pathways often hyperactive in human cancers, including nuclear factor-κB, Akt, signal transducer and activator of transcription 3, and androgen receptor. The present study was designed to determine the role of Notch signaling, which is constitutively active in many human cancers, in anticancer effects of SFN using prostate cancer cells as a model. Exposure of human prostate cancer cells (PC-3, LNCaP, and/or LNCaP-C4-2B) to SFN as well as its naturally-occurring thio-, sulfinyl-, and sulfonyl-analogs resulted in cleavage (activation) of Notch1, Notch2, and Notch4, which was accompanied by a decrease in levels of full-length Notch forms especially at the 16- and 24-hour time points. The SFN-mediated cleavage of Notch isoforms was associated with its transcriptional activation as evidenced by RBP-Jk-, HES-1A/B- and HEY-1 luciferase reporter assays. Migration of PC-3 and LNCaP cells was decreased significantly by RNA interference of Notch1 and Notch2, but not Notch4. Furthermore, SFN-mediated inhibition of PC-3 and LNCaP cell migration was only marginally affected by knockdown of Notch1 and Notch2. Strikingly, SFN administration to Transgenic Adenocarcinoma of Mouse Prostate transgenic mice failed to increase levels of cleaved Notch1, cleaved Notch2, and HES-1 proteins in vivo in prostatic intraepithelial neoplasia, well-differentiated carcinoma or poorly-differentiated prostate cancer lesions. These results indicate that Notch activation is largely dispensable for SFN-mediated inhibition of cell migration, which should be viewed as a therapeutic advantage as Notch activation is frequent in human prostate cancers.
Highlights
IntroductionPrevious studies from our laboratory have shown that oral gavage of 6 mmol SFN (three times per week) beginning at 6–7 weeks of age significantly inhibited incidence and burden of prostatic intraepithelial neoplasia (PIN) and/or well-differentiated prostate cancer (WD) as well as pulmonary metastasis multiplicity in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without causing any side effects [8]
D, L-Sulforaphane (SFN), a synthetic racemic analog of broccoli-derived L-isomer (L-SFN), is a highly promising cancer chemopreventive agent with remarkable activity in preclinical animal models [1,2]
Previous studies from our laboratory have shown that oral gavage of 6 mmol SFN beginning at 6–7 weeks of age significantly inhibited incidence and burden of prostatic intraepithelial neoplasia (PIN) and/or well-differentiated prostate cancer (WD) as well as pulmonary metastasis multiplicity in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without causing any side effects [8]
Summary
Previous studies from our laboratory have shown that oral gavage of 6 mmol SFN (three times per week) beginning at 6–7 weeks of age significantly inhibited incidence and burden of prostatic intraepithelial neoplasia (PIN) and/or well-differentiated prostate cancer (WD) as well as pulmonary metastasis multiplicity in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without causing any side effects [8]. Consistent with these data [8], 8-week old TRAMP mice fed with 240 mg of broccoli sprouts/mouse/day exhibited a significant decrease in prostate tumor growth in another study [9]. Growth of PC-3 human prostate cancer cells xenografted in male athymic mice was retarded significantly by oral treatment with SFN [10]
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