Neelam Sharma-Walia

Targeted therapy is highly desirable, as it allows for selective cytotoxicity on diseased cells without off-target side effects. Nucleolin is a remarkable target for cancer therapy given its high abundance, selective presence on the plasma membrane, and multifaceted influence on the initiation and progression of cancer. Nucleolin is a protein overexpressed on the cell membrane in many tumors and serves as a binding protein for several ligands implicated in angiogenesis and tumorigenesis. Nucleolin is present in the cytoplasm, nucleoplasm, and nucleolus and is used by selected pathogens for cell entry. AS1411 is a guanosine-rich oligonucleotide aptamer that binds nucleolin and is internalized in the tumor cells. AS1411 is well tolerated at therapeutic doses and localizes to tumor cells overexpressing nucleolin. AS1411 has a good safety profile with efficacy in relapsed acute myeloid leukemia and renal cell carcinoma producing mild or moderate side effects. The promising potential of AS1411 is its ability to be conjugated to drugs and nanoparticles. When a drug is bound to AS1411, the drug will localize to tumor cells leading to targeted therapy with fewer systemic side effects than traditional practices. AS1411 can also be bound to nanoparticles capable of detecting nucleolin at concentrations far lower than lab techniques used today for cancer diagnosis. AS1411 has a promising potential to change cancer diagnoses and treatment.

Cyclopentenone prostaglandins (cyPGs) are biologically active lipid mediators, including PGA₂, PGA₁, PGJ₂, and its metabolites. cyPGs are essential regulators of inflammation, cell proliferation, apoptosis, angiogenesis, cell migration, and stem cell activity. cyPGs biologically act on multiple cellular targets, including transcription factors and signal transduction pathways. cyPGs regulate the inflammatory response by interfering with NF-κB, AP-1, MAPK, and JAK/STAT signaling pathways via both a group of nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) dependent and PPAR-γ independent mechanisms. cyPGs promote the resolution of chronic inflammation associated with cancers and pathogen (bacterial, viral, and parasitic) infection. cyPGs exhibit potent effects on viral infections by repressing viral protein synthesis, altering viral protein glycosylation, inhibiting virus transmission, and reducing virus-induced inflammation. We summarize their anti-proliferative, pro-apoptotic, cytoprotective, antioxidant, anti-angiogenic, anti-inflammatory, pro-resolution, and anti-metastatic potential. These properties render them unique therapeutic value, especially in resolving inflammation and could be used in adjunct with other existing therapies. We also discuss other α, β -unsaturated carbonyl lipids and cyPGs like isoprostanes (IsoPs) compounds.

The endoplasmic reticulum (ER) regulates protein folding, post-translational modifications, lipid synthesis, and calcium signaling to attenuate the accumulation of misfolded proteins causing ER stress and maintains cellular homeostasis. The tumor microenvironment is rich in soluble cytokines, chemokines, growth, and angiogenic factors and can drive the ER’s abnormal functioning in healthy cells. Cancer cells adapt well to the tumor microenvironment induced ER stress. We identified that the inflammatory breast cancer (IBC) cells abundantly express osteoprotegerin (OPG) and their tumor microenvironment is rich in OPG protein. OPG also called osteoclast differentiation factor/osteoclastogenesis inhibitory factor (OCIF) is a soluble decoy receptor for receptor activator of nuclear factor-kappa B ligand (RANKL). Employing mass spectrometry analysis, we identified a set of ER chaperones associated with OPG in IBC cell lysates (SUM149PT, SUM1315MO2) compared to healthy human mammary epithelial cells (HMEC). Proximity ligation assay (PLA) and immunoprecipitation assay validated the interaction between OPG and ER chaperone and master regulator of unfolded protein response (UPR) GRP78/BiP (glucose-regulated protein/Binding immunoglobulin protein). We detected remarkably high gene expression of CCAAT enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE1α), protein disulfide-isomerase (PDI), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP-1) and growth arrest and DNA damage-inducible protein (GADD34) in SUM149PT and SUM190PT cells when compared to HMEC. Similarly, tissue sections of human IBC expressed high levels of ER stress proteins. We evaluated cell death and apoptosis upon Salubrinal and phenylbutyrate treatment in healthy and IBC cells by caspase-3 activity and cleaved poly (ADP-ribose) polymerase (PARP) protein assay. IBC (SUM149PT and SUM190PT) cells were chemosensitive to Salubrinal treatment, possibly via inhibition in OPG secretion, upregulating ATF4, and CHOP, thus ultimately driving caspase-3 mediated IBC cell death. Salubrinal treatment upregulated PDI, which connects ER stress to oxidative stress. We observed increased ROS production and reduced cell proliferation of Salubrinal treated IBC cells. Treatment with antioxidants could rescue IBC cells from ROS and aborted cell proliferation. Our findings implicate that manipulating ER stress with Salubrinal may provide a safer and tailored strategy to target the growth of inflammatory and aggressive forms of breast cancer.

Herpesviruses utilize various host factors to establish latent infection, survival, and spread disease in the host. These factors include host cellular machinery, host proteins, gene expression, multiple transcription factors, cellular signal pathways, immune cell activation, transcription factors, cytokines, angiogenesis, invasion, and factors promoting metastasis. The knowledge and understanding of host genes, protein products, and biochemical pathways lead to discovering safe and effective antivirals to prevent viral reactivation and spread infection. Here, we focus on the contribution of pro-inflammatory, anti-inflammatory, and resolution lipid metabolites of the arachidonic acid (AA) pathway in the lifecycle of herpesvirus infections. We discuss how various herpesviruses utilize these lipid pathways to their advantage and how we target them to combat herpesvirus infection. We also summarize recent development in anti-herpesvirus therapeutics and new strategies proposed or under clinical trials. These anti-herpesvirus therapeutics include inhibitors blocking viral life cycle events, engineered anticancer agents, epigenome influencing factors, immunomodulators, and therapeutic compounds from natural extracts.

The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.

The latent-to-lytic switch in KSHV infection is one of the critical events regulated by the major replication and transcription activator KSHV protein called RTA. Chromatin modification of the viral genome determines the phase of the viral life cycle in the host. Here, we report that LXA4 interacts with a host chromatin modulator, especially SMARCB1, which upregulates the KSHV ORF50 promoter. SMARCB1 has also been recognized to be a tumor suppressor protein which controls many tumorigenic events associated with the hedgehog (hh) signaling pathway. We also observed that LXA4 treatment reduces PD-L1 expression and that PD-L1 expression is an important immune evasion strategy used by KSHV for its survival and maintenance in the host. Our study underscores the role of LXA4 in KSHV biology and emphasizes that KSHV is strategic in downregulating LXA4 secretion in the host to establish latency. This study also uncovers the therapeutic potential of LXA4 and its targetable receptor, AhR, in KSHV’s pathogenesis.

Small molecule chemotherapeutic agents such as Imatinib, Gefitinib, and Erlotinib have played a significant role in the treatment of cancer. Although the unprecedented progress has been achieved in cancer treatment with these targeted agents, there is a strong demand for the development of selective and highly efficacious cancer drugs. V-ATPases are emerging as important target for the identification of novel therapeutic agents for cancer. Our screening and drug discovery processes have identified the bisbenzimidazole derivative (RP-15) as a potent anticancer V-ATPase inhibitor. In the present study, bisbenzimidazoles (compound-25, RP-11 and RP-15) have been tested for proton-pump inhibition activity in human hepatoma cell line (Huh7.5). RP-15 displayed comparable proton-pump inhibition activity to the standard Bafilomycin A1. We examined the antiproliferative activity of these analogs in two highly invasive and metastatic inflammatory breast cancer (IBC) cell lines (SUM 149PT and SUM190PT) along with Huh7.5. The compound-25 (SUM190PT: IC50 = 0.43±0.11 μM) and its structural analog RP-11 (SUM190PT: IC50 = 0.49±0.09 μM) have shown significant inhibition toward IBC cell lines. Additionally, RP-11 and RP-15 have demonstrated very good cytotoxicity toward the majority of cancer cell lines in the NCI 60 cell line panel.

Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, particularly latent infection is often associated with inflammation. The arachidonic acid pathway, the home of several inflammation and resolution associated lipid mediators, is widely altered upon viral infections. Several in vitro studies show that these lipid mediators help in the progression of viral pathogenesis. This review summarizes the findings related to human herpesvirus KSHV infection and arachidonic acid pathway metabolites. KSHV infection has been shown to promote inflammation by upregulating cyclooxygenase-2 (COX-2), 5 lipoxygenase (5LO), and their respective metabolites prostaglandin E₂ (PGE₂) and leukotriene B4 (LTB₄) to promote latency and an inflammatory microenvironment. Interestingly, the anti-inflammatory lipid mediator lipoxin is downregulated during KSHV infection to facilitate infected cell survival. These studies aid in understanding the role of arachidonic acid pathway metabolites in the progression of viral infection, the host inflammatory response, and pathogenesis. With limited therapeutic options to treat KSHV infection, use of inhibitors to these inflammatory metabolites and their synthetic pathways or supplementing anti-inflammatory lipid mediators could be an effective alternative therapeutic.

Lipids play a fundamental role in maintaining normal function in healthy cells. Their functions include signaling, storing energy, and acting as the central structural component of cell membranes. Alteration of lipid metabolism is a prominent feature of cancer, as cancer cells must modify their metabolism to fulfill the demands of their accelerated proliferation rate. This aberrant lipid metabolism can affect cellular processes such as cell growth, survival, and migration. Besides the gene mutations, environmental factors, and inheritance, several infectious pathogens are also linked with human cancers worldwide. Tumor viruses are top on the list of infectious pathogens to cause human cancers. These viruses insert their own DNA (or RNA) into that of the host cell and affect host cellular processes such as cell growth, survival, and migration. Several of these cancer-causing viruses are reported to be reprogramming host cell lipid metabolism. The reliance of cancer cells and viruses on lipid metabolism suggests enzymes that can be used as therapeutic targets to exploit the addiction of infected diseased cells on lipids and abrogate tumor growth. This review focuses on normal lipid metabolism, lipid metabolic pathways and their reprogramming in human cancers and viral infection linked cancers and the potential anticancer drugs that target specific lipid metabolic enzymes. Here, we discuss statins and fibrates as drugs to intervene in disordered lipid pathways in cancer cells. Further insight into the dysregulated pathways in lipid metabolism can help create more effective anticancer therapies.

Water transport proteins–aquaporins (AQPs) in cancer biology Water transport proteins–aquaporins (AQPs) in cancer biology