Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.
Lindsay G Carter, John A D'Orazio and Kevin J Pearson
W Solarek, A M Czarnecka, B Escudier, Z F Bielecka, F Lian and C Szczylik
Insulin and IGFs play a significant role in cancer development and progression, including renal cell carcinoma (RCC). RCC is the most frequent type of kidney cancer in adults and the tenth most common malignancy worldwide. Insulin is normally associated with metabolism control, whereas IGFs are defined as proliferation regulators. Today, there is convincing evidence of an association between obesity and the risk of RCC. Indicated risk factors together with type 2 diabetes are irreversibly connected with circulating insulin and IGF levels. The interplay between these molecules, their receptors, and IGF-binding proteins might be crucial for RCC cell biology and RCC progression. Given the potent activity IGF/IGF receptor 1 (IGF1R) inhibitors demonstrate against RCC in basic research, some type of combination therapy may prove to be beneficial clinically in the management of RCC. This review addresses not only molecular but also clinical associations between insulin and IGF1 signaling pathways and both RCC biology and clinical course. Revealing these interactions may improve our understanding of basic molecular oncology processes in RCC and improve treatment strategies.
Prostate cancer (PC) is the most common malignancy in males. It is evident that genetic factors at both germline and somatic levels play critical roles in prostate carcinogenesis. Recently, genome-wide association studies (GWAS) by high-throughput genotyping technology have identified more than 70 germline variants of various genes or chromosome loci that are significantly associated with PC susceptibility. They include multiple 8q24 loci, prostate-specific genes, and metabolism-related genes. Somatic alterations in PC genomes have been explored by high-throughput sequencing technologies such as whole-genome sequencing and RNA sequencing, which have identified a variety of androgen-responsive events and fusion transcripts represented by E26 transformation-specific (ETS) gene fusions. Recent innovations in high-throughput genomic technologies have enabled us to analyze PC genomics more comprehensively, more precisely, and on a larger scale in multiple ethnic groups to increase our understanding of PC genomics and biology in germline and somatic studies, which can ultimately lead to personalized medicine for PC diagnosis, prevention, and therapy. However, these data indicate that the PC genome is more complex and heterogeneous than we expected from GWAS and sequencing analyses.
P E Goss
Third-generation aromatase inhibitors are able to reduce circulating plasma estrogen concentrations in postmenopausal women to below detectable limits and significantly inhibit aromatase, the enzyme responsible for estrogen synthesis, in normal breast tissue and breast tumors. Their role in the treatment of advanced breast cancer is well established and their use in adjuvant therapy is currently being explored. On the basis of these trials, evaluation of these inhibitors in the prevention of breast cancer may be appropriate. Aromatase inhibitors have non-specific toxic side effects including (but not limited to): asthenia, headache, nausea, peripheral edema, fatigue, vomiting and dyspepsia. In addition, certain endocrinological side effects in postmenopausal women are notable, namely hot flushes and vaginal dryness. In advanced breast cancer, these side effects result in treatment withdrawal in few (<4%) women. Of concern, however, are the potential long-term endocrinological side effects in women receiving treatment as first-line adjuvant therapy or in sequence or combination with tamoxifen or other selective estrogen receptor modulators (SERMs). Current studies of adjuvant treatments for breast cancer in healthy women are carefully evaluating, in addition to general toxicities, the effects on bone, lipid metabolism, cardiovascular risk, quality of life and menopausal symptoms. Careful evaluation of all-cause morbidity and mortality is necessary to plan trials and justify long-term use of aromatase inhibitors in the treatment or prevention of breast cancer in healthy women.
Filipa Morais-Santos, Vera Miranda-Gonçalves, Sílvia Pinheiro, André F Vieira, Joana Paredes, Fernando C Schmitt, Fátima Baltazar and Céline Pinheiro
The tumour microenvironment is known to be acidic due to high glycolytic rates of tumour cells. Monocarboxylate transporters (MCTs) play a role in extracellular acidification, which is widely known to be involved in tumour progression. Recently, we have described the upregulation of MCT1 in breast carcinomas and its association with poor prognostic variables. Thus, we aimed to evaluate the effect of lactate transport inhibition in human breast cancer cell lines. The effects of α-cyano-4-hydroxycinnamate, quercetin and lonidamine on cell viability, metabolism, proliferation, apoptosis, migration and invasion were assessed in a panel of different breast cancer cell lines. MCT1, MCT4 and CD147 were differently expressed among the breast cancer cell lines and, as expected, different sensitivities were observed for the three inhibitors. Interestingly, in the most sensitive cell lines, lactate transport inhibition induced a decrease in cell proliferation, migration and invasion, as well as an increase in cell death. Results were validated by silencing MCT1 expression using siRNA. The results obtained here support targeting of lactate transport as a strategy to treat breast cancer, with a special emphasis on the basal-like subtype, which so far does not have a specific molecular therapy.
A Stigliano, L Cerquetti, M Borro, G Gentile, B Bucci, S Misiti, P Piergrossi, E Brunetti, M Simmaco and V Toscano
Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chloro-phenyl) ethane (o,p′-DDD), is a compound that represents the effective agent in the treatment of the adrenocortical carcinoma (ACC), able to block cortisol synthesis. In this type of cancer, the biological mechanism induced by this treatment remains still unknown. In this study, we have already shown a greater impairment in the first steps of the steroidogenesis and recognized a little effect on cell cycle. We also evaluated the variation of proteomic profile of the H295R ACC cell line, either in total cell extract or in mitochondria-enriched fraction after treatment with mitotane. In total cell extracts, triose phosphate isomerase, α-enolase, D-3-phosphoglycerate dehydrogenase, peroxiredoxin II and VI, heat shock protein 27, prohibitin, histidine triad nucleotide-binding protein, and profilin-1 showed a different expression. In the mitochondrial fraction, the following proteins appeared to be down regulated: aldolase A, peroxiredoxin I, heterogenous nuclear ribonucleoprotein A2/B1, tubulin-β isoform II, heat shock cognate 71 kDa protein, and nucleotide diphosphate kinase, whereas adrenodoxin reductase, cathepsin D, and heat shock 70 kDa protein 1A were positively up-regulated. This study represents the first proteomic study on the mitotane effects on ACC. It permits to identify some protein classes affected by the drug involved in energetic metabolism, stress response, cytoskeleton structure, and tumorigenesis.
Na Li, Huanni Li, Lanqin Cao and Xianquan Zhan
Mitochondria play important roles in growth, signal transduction, division, tumorigenesis and energy metabolism in epithelial ovarian carcinomas (EOCs) without an effective biomarker. To investigate the proteomic profile of EOC mitochondrial proteins, a 6-plex isobaric tag for relative and absolute quantification (iTRAQ) proteomics was used to identify mitochondrial expressed proteins (mtEPs) in EOCs relative to controls, followed by an integrative analysis of the identified mtEPs and the Cancer Genome Atlas (TCGA) data from 419 patients. A total of 5115 quantified proteins were identified from purified mitochondrial samples, and 262 proteins were significantly related to overall survival in EOC patients. Furthermore, 63 proteins were identified as potential biomarkers for the development of an EOC, and our findings were consistent with previous reports on a certain extent. Pathway network analysis identified 70 signaling pathways. Interestingly, the results demonstrated that cancer cells exhibited an increased dependence on mitophagy, such as peroxisome, phagosome, lysosome, valine, leucine and isoleucine degradation and fatty acid degradation pathways, which might play an important role in EOC invasion and metastasis. Five proteins (GLDC, PCK2, IDH2, CPT2 and HMGCS2) located in the mitochondrion and enriched pathways were selected for further analysis in an EOC cell line and tissues, and the results confirmed reliability of iTRAQ proteomics. These findings provide a large-scale mitochondrial proteomic profiling with quantitative information, a certain number of potential protein biomarkers and a novel vision in the mitophagy bio-mechanism of a human ovarian carcinoma.
Zhi Long, Yinan Li, Yu Gan, Dongyu Zhao, Guangyu Wang, Ning Xie, Jessica M Lovnicki, Ladan Fazli, Qi Cao, Kaifu Chen and Xuesen Dong
Homeobox A10 (HOXA10) is an important transcription factor that regulates the development of the prostate gland. However, it remains unknown whether it modulates prostate cancer (PCa) progression into castrate-resistant stages. In this study, we have applied RNA in situ hybridization assays to demonstrate that downregulation of HOXA10 expression is associated with castrate-resistant PCa. These findings are supported by public RNA-seq data showing that reduced HOXA10 expression is correlated with poor patient survival. We show that HOXA10 suppresses PCa cell proliferation, anchorage colony formation and xenograft growth independent to androgens. Using AmpliSeq transcriptome sequencing, we have found that gene groups associated with lipid metabolism and androgen receptor (AR) signaling are enriched in the HOXA10 transcriptome. Furthermore, we demonstrate that HOXA10 suppresses the transcription of the fatty acid synthase (FASN) gene by forming a protein complex with AR and prevents AR recruitment to the FASN gene promoter. These results lead us to conclude that downregulation of HOXA10 gene expression may enhance lipogenesis to promote PCa cell growth and tumor progression to castrate-resistant stage.
José O Alemán, Azeez Farooki and Monica Girotra
Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.
Atsushi Mizokami, Eitetsu Koh, Kouji Izumi, Kazutaka Narimoto, Masashi Takeda, Seijiro Honma, Jinlu Dai, Evan T Keller and Mikio Namiki
One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5α-reductase inhibitor dutasteride appears to function not only as a 5α-reductase inhibitor but also as a 3β-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis.