Petra Buchwald Hunziker

Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate

Epidemiological evidence links consumption of lycopene, the red carotenoid of tomato, to reduced prostate cancer risk. We investigated the effect of lycopene in normal prostate tissue to gain insight into the mechanisms, by which lycopene can contribute to primary prostate cancer prevention. We supplemented young rats with 200 ppm lycopene for up to 8 wk, measured the uptake into individual prostate lobes, and analyzed lycopene‐induced gene regulations in dorsal and lateral lobes after 8 wk of supplementation. Lycopene accumulated in all four prostate lobes over time, with all‐trans lycopene being the predominant isoform. The lateral lobe showed a significantly higher total lycopene content than the other prostate lobes. Transcriptomics analysis revealed that lycopene treatment mildly but significantly reduced gene expression of androgen‐metabolizing enzymes and androgen targets. Moreover, local expression of IGF‐I was decreased in the lateral lobe. Lycopene also consistently reduced transcript levels of proinflammatory cytokines, immunoglobulins, and immunoglobulin receptors in the lateral lobe. This indicates that lycopene reduced inflammatory signals in the lateral prostate lobe. In summary, we show for the first time that lycopene reduced local prostatic androgen signaling, IGF‐I expression, and basal inflammatory signals in normal prostate tissue. All of these mechanisms can contribute to the epidemiologically observed prostate cancer risk reduction by lycopene.

β-Carotene-Induced Changes in RARβ Isoform mRNA Expression Patterns Do Not Influence Lung Adenoma Multiplicity in the NNK-Initiated A/J Mouse Model

Abstract: A number of epidemiological studies have reported associations of β-carotene plasma levels or intake with decreased lung cancer risk. However, intervention studies in smokers reported increased lung tumor rates after high long-term β-carotene supplementation. For insight into these conflicting results, we studied the influence of β-carotene on tobacco smoke carcinogen-induced lung cancer development in the A/J-mouse using 4-(N-Methyl-N-nitro samino)-1-(3-pyridyl)-1-butanone (NNK) as the initiator and lung adenoma multiplicity as the functional endpoint. Gene regulation of the putative tumor suppressor RARβ in mouse lung was analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for its relevance in predicting the endpoint of lung cancer. A/J-mice achieved plasma β-carotene levels of up to 3 μmol/L within 4 wk and up to 6 μmol/L after 6 mo of supplementation on a diet modified to enhance β-carotene absorption. Despite high lung β-carotene concentrations of up to 6 μmol/kg, tumor multiplicity was not significantly affected by the β-carotene treatment, either in carcinogen-initiated or non-initiated mice, and was unrelated to β-carotene dose and the time point of treatment during cancer formation. Tumor multiplicity did not correlate with β-carotene plasma levels in NNK-treated animals. All RARβ isoforms were significantly suppressed in the lungs of NNK- and NNK plus high dose β-carotene-treated animals. However, the number of tumors per mouse did not correlate with the RARβ-isoform expression levels. β-carotene alone after 3 mo of supplementation mildly but significantly increased levels of RARβ1, β2, and β4. This increase persisted for 6 mo for RARβ2 and β4. In summary, we found no effect of β-carotene on tumor formation in the NNK-initiated A/J-mouse lung cancer model with respect to dose or time point of treatment. β-Carotene-induced changes in RARβ isoform gene expression levels were not predictive for the number of lung tumors but were indicative of intact β-carotene metabolism and persistent sensitivity to retinoic acid in the mice. Down-regulation of RARβ in NNK-induced adenoma-bearing lungs was similar to that observed in human lung cancer and further confirms the A/J-mouse as a valuable model for lung carcinogenesis.

β-Carotene interference with UVA-induced gene expression by multiple pathways

UVA exposure causes skin photoaging by singlet oxygen (1O2)-mediated induction of matrix metalloproteases (MMPs). We assessed whether β-carotene, a carotenoid known as 1O2 quencher and retinoic acid (RA) precursor, interferes with UVA-induced gene regulation and prevents UVA-induced gene regulation in HaCaT human keratinocytes. HaCaT cells accumulated β-carotene in a time- and dose-dependent manner. UVA irradiation massively reduced the cellular β-carotene contents. β-Carotene suppressed UVA induction of MMP-1, MMP-3, and MMP-10 - three major MMPs involved in photoaging. HaCaT cells produced weak retinoid activity from β-carotene, as demonstrated by mild up-regulation of retinoid receptor RARβ and activation of an RARE-dependent reporter gene. Of the 568 UVA-regulated genes, β-carotene reduced the UVA effect for 143, enhanced it for 180, and did not interact with UVA for 245 genes. The pathways regulated β-carotene in interaction with UVA were characterized by genes involved in growth factor signaling, stress response, apoptosis, cell cycle, extracellular matrix (ECM) degradation, tanning, and inflammation. In conclusion, β-carotene at physiological concentrations interacted with UVA effects by multiple mechanisms that included, but were not restricted to, 1O2 quenching. With our results, we provide a mechanistic basis for the long-known and clinically established photoprotective effects of β-carotene in human skin.