Signal transducer and activator of transcription 3 (STAT3) plays important roles in multiple aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor cell immune evasion by regulating the expression of multiple downstream target genes. STAT3 is constitutively activated in many malignant tumors and its activation is associated with high histological grade and advanced cancer stages. Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced and metastatic cancers. Herein, we identified a STAT3 inhibitor, inS3-54, by targeting the DNA-binding domain of STAT3 using an improved virtual screening strategy. InS3-54 preferentially suppresses proliferation of cancer over non-cancer cells and inhibits migration and invasion of malignant cells. Biochemical analyses show that inS3-54 selectively inhibits STAT3 binding to DNA without affecting the activation and dimerization of STAT3. Furthermore, inS3-54 inhibits expression of STAT3 downstream target genes and STAT3 binding to chromatin in situ. Thus, inS3-54 represents a novel probe for development of specific inhibitors targeting the DNA-binding domain of STAT3 and a potential therapeutic for cancer treatments.
Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery. However, a US Food and Drug Administration (FDA)-approved drug targeting survivin has yet to emerge. In this Foundation Review, we examine and evaluate various strategies that have been used to target survivin and the stages of each survivin inhibitor to help understand this lack of success. We also provide future perspectives moving forward in targeting survivin for drug discovery.
Signal transducer and activator of transcription 3 (STAT3) controls many biological processes including differentiation, survival, proliferation, and angiogenesis. In normal healthy cells, STAT3 is tightly regulated to maintain a momentary active state. However, aberrant or constitutively activated STAT3 has been observed in many different cancers and constitutively activated STAT3 has been shown to associate with poor prognosis and tumor progression. For this reason, STAT3 has been studied as a possible target in the treatment of many different types of cancers. However, despite decades of research, a FDA-approved STAT3 inhibitor has yet to emerge. In this review, we will analyze past studies targeting STAT3 for drug discovery, understand possible causes of failure in these studies, and provide potential insights for future efforts to overcome these roadblocks.
Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule-based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. Cancer Res; 76(2); 453-62. Ó2016 AACR.
Fatty acid synthase (FASN), the sole cytosolic mammalian enzyme for de novo lipid synthesis, is crucial for cancer cell survival and associates with poor prognosis. FASN overexpression has been found to cause resistance to genotoxic insults. Here we tested the hypothesis that FASN regulates DNA repair to facilitate survival against genotoxic insults and found that FASN suppresses NF-κB but increases specificity protein 1 (SP1) expression. NF-κB and SP1 bind to a composite element in the poly(ADP-ribose) polymerase 1 (PARP-1) promoter in a mutually exclusive manner and regulate PARP-1 expression. Up-regulation of PARP-1 by FASN in turn increases Ku protein recruitment and DNA repair. Furthermore, lipid deprivation suppresses SP1 expression, which is able to be rescued by palmitate supplementation. However, lipid deprivation or palmitate supplementation has no effect on NF-κB expression. Thus, FASN may regulate NF-κB and SP1 expression using different mechanisms. Altogether, we conclude that FASN regulates cellular response against genotoxic insults by up-regulating PARP-1 and DNA repair via NF-κB and SP1.fatty acid synthase | transcription regulation | DNA repair | drug resistance | radiation resistance F atty acid synthase (FASN) is the key mammalian enzyme required for de novo synthesis of palmitate. FASN expression and activity are largely suppressed by sufficient dietary fat in most normal nonadipose tissues but are abnormally elevated in many human cancers and associated with poor prognosis (1). FASN association with poor prognosis may derive in part from FASN function in drug resistance during chemotherapy. Indeed, it has been found that FASN expression and/or activity was increased in drug-selected and -resistant breast (2) and pancreatic (3) cancer cells. It was also found that FASN overexpression causes cellular resistance to DNA-damaging drugs such as doxorubicin and mitoxantrone but not to microtubule modulators such as vinblastine and paclitaxel (4). Decreased ceramide production following doxorubicin treatment via suppression of tumor necrosis factor (TNF)-α production is believed to be one of the mechanisms of FASN-induced resistance to doxorubicin (4).The observation that FASN increases resistance to genotoxic drugs prompted us to hypothesize that FASN overexpression may up-regulate DNA damage response/repair pathways. In this study, we tested this hypothesis with a focus on the repair of DNA double-strand breaks (DSBs), which are commonly induced by the anticancer drugs doxorubicin and mitoxantrone and ionizing radiation. In mammalian cells, DSBs are repaired mainly via homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. NHEJ is the predominant form of DSB repair because it occurs during all phases of the cell cycle whereas HR only initiates at late G1 and S phases (5). Hence, we examined NHEJ repair of DSBs and found that FASN up-regulates NHEJ activity and repair of DSBs by increasing poly(ADP-ribose) polymerase 1 (PARP-1) expression via increasing the expression of spec...
Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clinical use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compounds may be acting on cancer cells.
The nucleotide excision repair pathway catalyzes the removal of bulky adduct damage from DNA and requires the activity of more than 30 individual proteins and complexes. A diverse array of damage can be recognized and removed by the NER pathway including UV-induced adducts and intrastrand adducts induced by the chemotherapeutic compound cisplatin. The recognition of DNA damage is complex and involves a series of proteins including the xeroderma pigmentosum group A and C proteins and the UV-damage DNA binding protein. The xeroderma pigmentosum group A protein is unique in the sense that it is required for both transcription coupled and global genomic nucleotide excision repair. In addition, xeroderma pigmentosum group A protein is required for the removal of all types of DNA lesions repaired by nucleotide excision repair. Considering its importance in the damage recognition process, the minimal information available on the mechanism of DNA binding and the potential that inhibition of xeroderma pigmentosum group A protein could enhance the therapeutic efficacy of platinum based anticancer drugs, we sought to identify and characterize small molecule inhibitors of the DNA binding activity of the xeroderma pigmentosum group A protein. In silico screening of a virtual small molecule library resulted in the identification of a class of molecules confirmed to inhibit the xeroderma pigmentosum group A protein-DNA interaction. Biochemical analysis of inhibition with varying DNA substrates revealed a common mechanism of xeroderma pigmentosum group A protein DNA binding to single-stranded DNA and cisplatin-damaged DNA.
Many proteins exist and function as oligomers. While hydrophobic interactions have been recognized as the major driving force for oligomerization, detailed molecular mechanisms for the assembly are unknown. Here, we used 14-3-3σ as a model protein and investigated the role of hydrophobic residues at the dimeric interface using MD simulations and coimmunoprecipitations. We found that a half-exposed and half-buried residue in the interface, Phe25, plays a more important role in promoting homodimerization than the hydrophobic core residues by organizing both favorable hydrophobic and hydrophilic interactions. Phe25 is critical in packing and stabilizing hydrophobic core residues. We conclude that the structural stability of hydrophobic cores is critical for a stable homodimer complex and this stable property can be bestowed by residues outside of hydrophobic core. The important organizing activity of Phe25 for homodimerization of 14-3-3σ originates from its unique physical location, rigidity, size, and hydrophobicity. Thus, hydrophobic residues that are not deeply buried at the oligomeric interface may play important but different roles from the buried core residues and they may promote oligomerization by organizing co-operativity of core and other residues for favorable hydrophobic and electrostatic interactions.
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