Experimental & Developmental TherapeuticsResearch Highlights
Abbreviation used: HMI, Hematopoiesis, Hematological Malignancies and Immunology
Dr. Lindsey Mayo investigating how the oncogene human murine double minute (Hdm2) is elevated in late-stage metastatic breast cancer discovered a novel pathway to induce its expression. Hdm2 regulates p53 stability via ubiquitination and Hdm2 has also been implicated in promoting the growth function of TGF-ß1. TGF-ß1 is a cytokine that has been implicated in stimulating tumor progression. Whether TGF-ß1 signaling induces Hdm2 expression leading to Hdm2-mediated destabilization of p53 has not been investigated. Drs. Mayo, Karen Pollok (HMI) and colleagues reported that TGF-ß1–activated Smad3/Smad4 (Smad3/4) transcription factors specifically bound to the second promoter region of Hd2, leading to increased Hdm2 protein expression and destabilization of p53 in human cancer cell lines. Additionally, TGF-ß1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithelial cells during epithelial-to-mesenchymal transition (EMT). Further, histological analyses of human breast cancer samples demonstrated that approximately 65 percent of late-stage carcinomas were positive for activated Smad3 and Hdm2, indicating a strong correlation between TGF-ß1–mediated induction of Hdm2 and late-stage tumor progression. Identification of Hdm2 as a downstream target of TGF-ß1 represents a critical pro-survival mechanism in cancer progression and provides another point for therapeutic intervention in late-stage cancer.
Targeting uncontrolled cell proliferation and resistance to DNA-damaging chemotherapeutics with a single agent has significant potential in cancer treatment. Replication protein A (RPA), the eukaryotic ssDNA-binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. Dr. John Turchi identified a novel small molecule that inhibits the in vitro and cellular ssDNA-binding activity of RPA, prevents cell cycle progression, induces cytotoxicity and increases the efficacy of chemotherapeutic DNA-damaging agents. These results provide new insight into the mechanism of RPA-ssDNA interactions in chromosome maintenance and stability. This represents the first molecularly targeted eukaryotic DNA-binding inhibitor and reveals the utility of targeting a protein-DNA interaction as a therapeutic strategy for cancer treatment.
Although approximately 50 percent of all types of human cancers harbor wild type TP53, this p53 tumor suppressor is often deactivated through a concerted action by its abnormally elevated suppressors: Mdm2, Mdmx, or SIRT1. Thus, targeting this p53-negating pathway is an attractive approach to identify small molecules that could kill cancerous cells. Drs. Samy Meroueh, Qizhuang Ye and colleagues dentified a small molecule called Inauhzin that can suppress tumor cell growth by activating p53 in both cell-based and animal model systems. Inauhzin can effectively stabilize and reactivate p53 by inhibiting SIRT1 activity as well as promote p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Remarkably, Inauhzin inhibits cell proliferation, induces tumor-specific apoptosis and represses the growth of xenograft tumors derived from p53-harboring H460 and HCT116 cells without causing apparent toxicity to the tumor-bearing SCID mice. It is a novel anti-cancer therapeutic candidate that will be potentially useful for human lung and colon cancers as well as other cancers that harbor wild type, but inactive, p53.