Balney Rajitha

Molecular cloning and sequence of retinoid X receptor in the green crab Carcinus maenas: a possible role in female reproduction

Retinoid X receptor (RXR) belongs to an ancient superfamily of nuclear hormone receptors, and plays an important role in reproduction of vertebrates. However, the reproductive role of RXR has not been clarified in crustaceans. In this investigation, we first report the cloning of two alternative splice variants of RXR cDNA from green crab ovarian RNA. RXR mRNA levels were quantified in different vitellogenic stages of the crab hepatopancreas (HP) and ovary. The expression of RXR mRNA relative to the arginine kinase mRNA was significantly increased in the HP of vitellogenic crabs in a stage-dependent manner. The relative levels of RXR mRNA in the ovary were significantly lower in vitellogenic stage III crabs than in crabs in the other three stages. These data indicate that the HP and ovary of the crab are capable of expressing RXR, which may regulate, in part, vitellogenesis in the crab. We also examined the effects of methyl farnesoate (MF) and RXR-dsRNA treatments on vitellogenin and RXR gene expression. Vitellogenin and RXR mRNA levels in HP and ovarian fragments incubated in MF were significantly (P<0.001) higher than in control tissue fragments prepared from the same animal. Treatment of crabs with RXR-dsRNA significantly (P<0.001) reduced mRNA levels for RXR and for vitellogenin as well as MF levels in hemolymph. These results indicate that, MF and RXR form a complex (MF-RXR) directly and together stimulate ovarian development in these green crabs. This interaction of RXR, MF, and ovary development axis is a novel finding and is the first report to the best of our knowledge.

Matrix metalloproteinases: Their functional role in lung cancer

Lung malignancy is the foremost cause of cancer-related deaths globally and is frequently related to long-term tobacco smoking. Recent studies reveal that the expression of matrix metalloproteinases (MMPs) is extremely high in lung tumors compared with non-malignant lung tissue. MMPs are zinc-dependent proteases and are involved in the degradation of extracellular matrix (ECM). Several investigations have shown that MMPs manipulate the activity of non-ECM molecules, including cytokines, growth factors and receptors that control the tumor microenvironment. In this review, we have summarized and critically reviewed the published works on the role of MMPs in non-small-cell lung cancer. We have also explored the structure of MMPs, their various types and roles in lung cancer metastasis including invasion, migration and angiogenesis.

Inhibition of NF-κB translocation by curcumin analogs induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer

Cell cycle progression and DNA synthesis are essential steps in cancer cell growth and resistance. Thymidylate synthase (TS) is a therapeutic target for 5FU. Curcumin is a potent inhibitor of NF-κB. EF31 and UBS109 are potent synthetic analogues of curcumin. We tested the hypothesis that inhibition of NF-κB translocation by curcumin and its analogs EF31 and UBS109 can inhibit cell cycle progression and downregulate TS levels in colorectal cancer (CRC) cell lines. Two CRC cell lines (HCT116 and HT-29) were either untreated (control) or treated with IC50 concentrations of curcumin, EF31 UBS109 led to G0/G1 cell cycle arrest. Treatment with curcumin, EF31 or UBS109 inhibited NF-κB, downregulated survival pathways and inhibited cell cycle progression. Arrest in the G0/G1 phase was associated with downregulation of the transcription factor E2F-1 and its target gene TS. NF-κB over-expression induced E2F-1 and TS protein and mRNA levels in both cell lines. EF31 and UBS109 treatment significantly decreased tumor growth in compared to untreated tumors. EF31 and UBS109 are promising agents for the prevention and treatment of CRC.

The role of adiponectin in obesity-associated female-specific carcinogenesis

Adipose tissue is a highly vascularized endocrine organ, and its secretion profiles may vary with obesity. Adiponectin is secreted by adipocytes that make up adipose tissue. Worldwide, obesity has been designated a serious health problem among women and is associated with a variety of metabolic disorders and an increased risk of developing cancer of the cervix, ovaries, uterus (uterine/endometrial), and breast. In this review, the potential link between obesity and female-specific malignancies is comprehensively presented by discussing significant features of the intriguing and complex molecule, adiponectin, with a focus on recent findings highlighting its molecular mechanism of action in female-specific carcinogenesis.

Aquaporins: Their role in gastrointestinal malignancies

Aquaporins (AQPs) are small (~30 kDa monomers) integral membrane water transport proteins that allow water to flow through cell membranes in reaction to osmotic gradients in cells. In mammals, the family of AQPs has thirteen (AQP0-12) unique members that mediate critical biological functions. Since AQPs can impact cell proliferation, migration and angiogenesis, their role in various human cancers is well established. Recently, AQPs have been explored as potential diagnostic and therapeutic targets in gastrointestinal (GI) cancers. GI cancers encompass multiple sites including the colon, esophagus, stomach and pancreas. Research in the last three decades has revealed biological aspects and signaling pathways critical for the development of GI cancers. Since the majority of these cancers are very aggressive and rapidly metastasizes, identifying effective targets is crucial for treatment. Preclinical studies have utilized inhibitors of specific AQPs and knock down of AQP expression using siRNA. Although several studies have explored the role of AQPs in colorectal, esophageal, gastric, hepatocellular and pancreatic cancers, there is no comprehensive review compiling the available information on GI cancers as has been published for other malignancies such as ovarian cancer. Due to the similarities and association of various sites of GI cancers, it is helpful to consider these results collectively in order to better understand the role of specific AQPs in critical GI cancers. This review summarizes the current knowledge of the role of AQPs in GI malignancies with particular focus on diagnosis and therapeutic applications.

Structural prediction and analysis of VIH-related peptides from selected crustacean species.

The tentative elucidation of the 3D-structure of vitellogenesis inhibiting hormone (VIH) peptides is conversely underprivileged by difficulties in gaining enough peptide or protein, diffracting crystals, and numerous extra technical aspects. As a result, no structural information is available for VIH peptide sequences registered in the Genbank. In this situation, it is not surprising that predictive methods have achieved great interest. Here, in this study the molt-inhibiting hormone (MIH) of the kuruma prawn (Marsupenaeus japonicus) is used, to predict the structure of four VIHrelated peptides in the crustacean species. The high similarity of the 3D-structures and the calculated physiochemical characteristics of these peptides suggest a common fold for the entire family.

MicroRNAs as biomarkers and prospective therapeutic targets in colon and pancreatic cancers

Colon and pancreatic cancers have high mortality rates due to early metastasis prior to the onset of symptoms. Screening tests for colorectal cancer are invasive and expensive. No effective screening is available for pancreatic cancer. Identification of biomarkers for early detection in both of these cancers is being extensively researched. MicroRNAs (miRNA) are small non-coding molecule biomarkers that regulate cancers. Measurement of miRNAs in pancreatic fluid or blood could be a preferred non-invasive screening method. The regulation of colon and pancreatic cancers by miRNA is complex. miRNA play a central role in inflammation, invasiveness, and tumor progression in these two cancers, as well as regulation of the NF-κB pathway. miRNA’s evolving role in screening is also reviewed.

Curcumin and Genistein Role in Regulation of STAT-3 in Pancreatic Cancer

Pancreatic cancer (PC) is one of the most fatal malignant tumors across the world. STAT-3 is involved in PC growth and metastasis. STAT-3 is a transcription factor that regulates many oncogenic transduction pathways. In the current chapter, we discuss the importance of STAT-3 in hypoxia and hypoxia-inducible genes. Further, we also explore the inhibition of STAT-3 by phytochemicals such as curcumin and genistein.

Abstract 4416: Combination of HSP90 and proteasome inhibitor is effective in pancreatic cancer

Background: Heat shock protein (HSP90) and proteasome play an important role in cellular protein trafficking and degradation in pancreatic cancer (PC). Given the overlap in the mechanism of action, we investigated the effects of the combination of pharmacological inhibitors of HSP90 (Ganetespib) and proteasome (Carfilzomib) on PC cells in vitro and in vivo. Methods: The combined effects of ganetespib and carfilzomib were evaluated in MIA PaCa-2 and HPAC cell lines using a cell proliferation assay. Effects on the expression of survival (PI3K/AKT, and ERK), cell cycle (Cdc-2 and cyclin B1), angiogenesis (HIF-1α and VEGF) and autophagy (LC3 A/B, and Atg7) pathways were examined by Western blot. Cell cycle analysis was performed by FACS assay. HPAC cell lines were tested for efficacy to ganetespib, carfilzomib, alone and in combination, using an in vivo tumor xenograft model. Results: The combination of ganetespib and carfilzomib significantly decreased cell proliferation, induced G2-M cell cycle arrest and induced autophagy in both MIA PaCa-2 and HPAC cell lines. Ganetespib and carfilzomib also decreased the activation of ERK, PI3K/AKT, and autophagy signaling molecules (LC3 A/B, and Atg7). In animal models, ganetespib potentiated the effects of carfilzomib, as measured by tumor volume. Western blot analysis from tumors removed from animals confirmed the effects of ganetespib and carfilzomib on survival, cell cycle, autophagy and angiogenesis. Conclusion: These observations provide preclinical proof-of-principle that combinatorial targeting of HSP90 and proteasome is a rational approach for development in PC clinical trials. Citation Format: Ganji Purnachandra Nagaraju, Balney Rajitha, Leah Benton, Bassel F. El-Rayes. Combination of HSP90 and proteasome inhibitor is effective in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4416.