Abstract
BackgroundPhenethyl isothiocyanate (PEITC), present naturally in cruciferous vegetables, is a chemopreventive agent. It blocks initiation and post-initiation progression of carcinogenesis. Mechanism study in human prostate cancer cells revealed that PEITC is a dual inhibitor of aberrant DNA hypermethylation and histone deacetylases, reactivating silenced genes and regulating the androgen-mediated growth of tumor cells. The identity of the cellular organelle that initially interacts with PEITC has not been fully described.MethodsHuman prostate cancer LNCaP cells were exposed to PEITC and the effects on cellular fine structure examined by transmission electron microscopic studies. Alteration of mitochondrial membrane potential and cytochrome c release were evaluated as early events of apoptosis, and the TUNEL method for quantifying apoptotic cells. Mitochondria were isolated for determining their protein expression.ResultsUltrastructural analyses have revealed condensed mitochondria and a perturbed mitochondrial cristae structure, which assumed a rounded and dilated shape within 4-hours of PEITC contact, and became more pronounced with longer PEITC exposure. They presented as the most prominent intracellular alterations in the early hours. Mitochondria structure alterations were demonstrated, for the first time, with the isothiocyanates. An increase in the number of smooth endoplasmic reticulum and vacuoles were also noted that is consistent with the presence of autophagy. Early events of apoptosis were detected, with cytochrome c released along with the appearance of mitochondrial alteration. Mitochondrial membrane potential was disrupted within 18 hours of PEITC exposure, preceding the appearance of apoptotic cells with DNA strand breaks. In parallel, the expression of the mitochondrial class III ß-tubulin in the outer membrane, which associates with the permeability transition pore, was significantly reduced as examined with isolated mitochondria.ConclusionMitochondria may represent the organelle target of the isothiocyanates, indicating that the isothiocyanates may be mitochondria-interacting agents to inhibit carcinogenesis.
Highlights
Phenethyl isothiocyanate (PEITC), present naturally in cruciferous vegetables, is a chemopreventive agent
Mitochondrial structure alteration by an isothiocyanate A human prostate cancer cell line LNCaP was chosen for examining the effects of PEITC on cellular organelles since its cellular growth dependents on androgen, and the inhibitory effects of the PEITC has been demonstrated
The condensed mitochondria appeared as dense bodies with a dark matrix and translucent cristae, which were present after 4 hour (Figure 1B and B’) and 18 hour PEITC treatment (Figure 1C and C’)
Summary
Phenethyl isothiocyanate (PEITC), present naturally in cruciferous vegetables, is a chemopreventive agent. It blocks initiation and post-initiation progression of carcinogenesis. Mechanism study in human prostate cancer cells revealed that PEITC is a dual inhibitor of aberrant DNA hypermethylation and histone deacetylases, reactivating silenced genes and regulating the androgen-mediated growth of tumor cells. In the studies of prostate cancer, PEITC has been demonstrated as a dual inhibitor of DNA hypermethylation and histone deacetylases, reactivating silenced genes including the π-class glutathione S-transferase which is inactivated by aberrant DNA methylation in the vast majority of clinical prostate tumors [5]. The identity of the cellular organelle as the target in the initial interaction with PEITC, have not been fully described
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