Therapeutic implications of cancer stem cells in prostate cancer

Prostate cancer, one of the most frequently occurring cancers in men, is a heterogeneous disease involving multiple cell types within tumors. This tumor heterogeneity at least partly results from genomic instability leading to sub-clonal cellular differentiation. The differentiated cell populations originate from a small subset of cells with tumor-initiating and stem-like properties. These cells, termed prostate cancer stem cells(PCSCs), play crucial roles in disease progression, drug resistance, and relapse. This review discusses the origin, hierarchy, and plasticity of PCSCs;methods for isolation and enrichment of PCSCs;and various cellular and metabolic signaling pathways involved in PCSC induction and maintenance, as well as therapeutic targeting.

Anti-cancer effects of sitagliptin,vildagliptin,and exendin-4 on triple-negative breast cancer cells via mitochondrial modulation

Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis,but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line.We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase(AMPK),which activates the downstream transcription factors PGC-1α,PGC-1β,or FOXO1 for mitochondrial biogenesis;above-mentioned incretin-based therapies are also known to activate AMPK.This study evaluated the effects of sitagliptin,vildagliptin,and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis,were examined.Treatment with sitagliptin(100μM),vildagliptin(100μM),and exendin-4(10 nM)for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay,cell migration by scratch,and transwell migration assays,accompanied with marginal reduction in cell numbers along with the apoptotic appearance,the rate of apoptosis,and decreased lactate content in conditioned medium.These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio,increased MitoTracker green and red staining,and increased expression of transcription factors PGC-1α,NRF-1,NRF-2,TFAM,and HO-1.Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1μM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay.Thus,sitagliptin,vildagliptin,and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect.Therapeutic response was in the order of:sitagliptin>vildagliptin>exendin-4.

Partial genomic organization of ribosomal protein S7 gene from malaria vector Anopheles stephensi

In this study, we describe the partial genomic organization of ribosomal protein S7 gene isolated from the mosquito Anopheles stephensi. Initially a 558 bp partial cDNA sequence was amplified as precursor mRNA sequence containing 223 bp long intron. 5＇ and 3＇ end sequences were recovered using end specific rapid amplification of cDNA ends （RACE） polymerase chain reaction. The full-length cDNA sequence was 914 nucleotide long with an open reading frame capable of encoding 192 amino acid long protein with calculated molecular mass of 22174 Da and a pI point of 9.94. Protein homology search revealed 〉75% identity to other insect＇s S7 ribosomal proteins. Analysis of sequence alignment revealed several highly conserved domains, one of which is related to nuclear localization signal （NLS） region of human rpS7. Interestingly, intron nucleotide sequence comparison with A. gambiae showed a lesser degree of conservation as compared to coding and untranslated regions. Like this, early studies on the genomic organization and cDNA/ Expressed sequence tag analysis （EST） could help in genome annotation ofA. stephensi, and would be likely to be sequenced in the future.

Stress-related ecophysiology of members of the genus Rhodanobacter isolated from a mixed waste contaminated subsurface

This work examines the physiologic basis of stress tolerance in bacterial strains of the genus Rhodanobacter that dominate in the acidic and highly metal contaminated near-source subsurface zone of the Oak Ridge Integrated Field Research Challenge(ORIFRC)site.Tolerance of R.denitrificans to levels of different stresses were studied in synthetic groundwater medium and R2A broth.Two strains of R.denitrificans,strains 2APBS1T and 116-2,tolerate low to circumneutral pH(4–8),high Uranium(1 mmol/L),elevated levels of nitrate(400 mmol/L)and high NaCl(2.5%).A combination of physiologic traits,such as growth at low pH,increased growth in the presence of high organics concentration,and tolerance of high concentrations of nitrate,NaCl and heavy metals is likely responsible for dominance of Rhodanobacter at the ORIFRC site.Furthermore,extended incubation times and use of low carbon media,better approximating site groundwater conditions,are critical for accurate determination of stress responses.This study expands knowledge of the ecophysiology of bacteria from the genus Rhodanobacter and identifies methodological approaches necessary for acquiring accurate tolerance data.