Viral Particle-Mediated SAMHD1 Depletion Sensitizes Refractory Glioblastoma to DNA-Damaging Therapeutics by Impairing Homologous Recombination.

The current standard-of-care treatment for glioblastoma includes DNA damaging agents, γ-irradiation (IR) and temozolomide (TMZ). These treatments fail frequently and there is limited alternative strategy. Therefore, identifying a new therapeutic target is urgently needed to develop a strategy that improves the efficacy of the existing treatments.

New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors.

The pro-apoptotic tumor suppressor BIN1 inhibits the activities of the neoplastic transcription factor MYC, poly (ADP-ribose) polymerase-1 (PARP1), and ATM Ser/Thr kinase (ATM) by separate mechanisms. Although BIN1 deficits increase cancer-cell resistance to DNA-damaging chemotherapeutics, such as cisplatin, it is not fully understood when BIN1 deficiency occurs and how it provokes cisplatin resistance. Here, we report that the coordinated actions of MYC, PARP1, and ATM assist cancer cells in acquiring cisplatin resistance by deficits.

Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin.

The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive.

Endocrine disruptor exposure during development increases incidence of uterine fibroids by altering DNA repair in myometrial stem cells.

Despite the major negative impact uterine fibroids (UFs) have on female reproductive health, little is known about early events that initiate development of these tumors. Somatic fibroid-causing mutations in mediator complex subunit 12 (MED12), the most frequent genetic alterations in UFs (up to 85% of tumors), are implicated in transforming normal myometrial stem cells (MSCs) into tumor-forming cells, though the underlying mechanism(s) leading to these mutations remains unknown. It is well accepted that defective DNA repair increases the risk of acquiring tumor-driving mutations, though defects in DNA repair have not been explored in UF tumorigenesis.

The Dual Roles of MYC in Genomic Instability and Cancer Chemoresistance.

Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress.

Restoration of tumor suppressor functions by small-molecule inhibitors.

Over the last decades, accumulating data have advanced our understanding of the mechanism of action of tumor suppressor proteins and therapeutic strategies to restore tumor suppressor pathways have emerged as a promising approach for cancer therapy. Based on our recent findings on bridging integrator-1 (BIN1), we outline potential advantages and disadvantages of chemical activation of tumor suppressors.

To die, or not to die: E2F1 never decides by itself during serum starvation.

The adenovirus E2 promoter-binding factor-1 (E2F1) induces apoptosis in response to DNA damage and serum starvation. After DNA damage, E2F1 is phosphorylated by ataxia telangiectasia-mutated (ATM) kinase to promote apoptosis. However, precisely how serum starvation stimulates E2F1-induced apoptosis is unclear.

Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment.

Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway.

Identification of a novel effector domain of BIN1 for cancer suppression.

Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein with tumor suppressor properties. The protein interacts with and inhibits the c-MYC transcription factor through the BIN1 MYC-binding domain (MBD). However, in vitro colony formation assays have clearly demonstrated that the MBD is not essential for BIN1-mediated growth arrest.

c-MYC suppresses BIN1 to release poly(ADP-ribose) polymerase 1: a mechanism by which cancer cells acquire cisplatin resistance.

Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of cancer cells to cisplatin depended on BIN1 abundance, regardless of the p53 gene status.

Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism.

Adenovirus E1A oncogene transforms primary rodent fibroblasts in cooperation with activated Ras. Conversely, the c-Myc oncoprotein-binding tumor suppressor, Bin1, inhibits Ras/E1A-mediated cell transformation. Since E1A does not directly bind to and inhibit Bin1, the primary mechanism by which E1A counteracts Bin1 to liberate oncogenic c-Myc activity is poorly understood.

Induction of Fas (CD95/APO-1) ligand is essential for p53-dependent apoptosis in an in vitro renal carcinoma model system.

Purpose: The Fas/CD95/APO-1 ligand (FasL) is a death cytokine that binds to cell surface Fas/CD95/APO-1 receptor, yet a possible role of FasL expression in p53-dependent apoptosis is not fully understood in many human malignancies, including renal carcinoma.

Methods: By Northern blot and Western blot analyses, we determined the effect of p53 on the FasL and Fas receptor expression. To do this, we employed an in vitro renal carcinoma model system that was previously established by stably co-transfecting a temperature-sensitive mutant allele of the p53 tumor suppressor (ts-p53) with either the c-Myc oncogene or adenovirus E1A oncogene in baby rat kidney (BRK) epithelial cells.

Bin1 attenuation in breast cancer is correlated to nodal metastasis and reduced survival.

Clinical outcomes in breast cancer are likely influenced by modifier genes that affect tumor dormancy versus progression. The Bin1 gene encodes a nucleocytosolic adapter protein that suppresses neoplastic cell transformation and that is often attenuated in human breast carcinoma. Recent mouse genetic studies indicate that Bin1 loss cooperates with ras activation to drive progression of mammary carcinoma, establishing Bin1 as a negative modifier of tumor progression in breast cancer.