Biology subjects

Mivechi, N. F.

Publications and source records attributed to Mivechi, N. F..

2 recordsLinked to original sources

bioRxiv2019

Oncoprotein GT198 Vaccination Delays Tumor Growth in MMTV-PyMT Mice

Different effects of anticancer drugs between mouse and human have caused increasing concerns. A better understanding of cancer initiation between the two species is needed. We have previously identified an oncoprotein GT198 (PSMC3IP) in human breast cancer. In this report, we investigated GT198 in MMTV-PyMT mouse mammary gland tumors and found a reconcilable mechanism in human and mouse. Specifically, distinct tumor initiating stimuli in human and mouse result in a common GT198-mediated tumorigenic pathway in both species. Here we show, similar to human breast cancer even before a tumor appears, GT198 has overexpressed in mouse tumor stroma including pericyte stem cells, descendent adipocytes, fibroblasts, and myoepithelial cells. Using recombinant GT198 protein as an antigen, we vaccinated MMTV-PyMT mice and found that the GT198 vaccine delayed mouse tumor growth and reduced lung metastasis. The antitumor effects in vaccinated mice were linearly correlated with serum titers of GT198 antibody, which can recognize cell surface GT198 protein on viable tumor cells confirmed by FACS. Furthermore, tumor cells isolated from MMTV-PyMT mice were re-implanted into normal FVB/N mice, GT198+ tumor cells induced faster tumor growths than GT198- tumor cells. Together, this first study of GT198 vaccine in mouse showed its effectiveness in antitumor and anti-metastasis. The finding may accelerate future development of GT198 immunotherapy in human cancer. Our finding also indicates that even though distinct cancer-initiation stimuli exist between mouse and human, a common tumorigenic pathway mediated by oncoprotein GT198 is shared in both species.

cancer biology↗

bioRxiv2019

Oncoprotein GT198 is a direct target of taxol

Taxol (paclitaxel) is one of the most successful chemotherapeutic drugs in the treatment of human cancer. It has recently been questioned whether the mechanism of action in mitotic arrest, which is ubiquitously present in all cells, is sufficient to explain the tumor specificity, clinical efficacy, and side effects of taxol. In this report, we have identified a new protein target of taxol as GT198 (gene symbol PSMC3IP, also known as Hop2). GT198 is an oncoprotein and a DNA repair factor involved in human common solid tumors. The GT198 gene carries germline mutations in breast and ovarian cancer families and recurrent somatic mutations in tumor microenvironment. Mutant GT198 was identified in pericyte stem cells on capillary blood vessels inducing tumor angiogenesis. GT198 is a DNA-binding protein dimer, also stimulates DNA repair, regulates meiosis, participates in homologous DNA recombination, and activates nuclear receptor-mediated gene expression. Here we show that taxol directly binds to the DNA-binding domain of GT198 in vitro. Taxol serves as an allosteric inhibitor to block DNA binding to GT198 with an IC50 of 8.6 nM. Labeled taxol colocalizes with GT198 in interphase nuclei of cultured cells. Decreased GT198 expression desensitizes taxolinduced cell death, and taxol inhibits GT198 nuclear foci formation during DNA repair. Together, these results demonstrate that GT198 is a previously unrecognized direct protein target of taxol. The finding of taxol target as an oncoprotein GT198 in common solid tumors provides a rationale for the clinical efficacy of taxol. We anticipate that GT198 may serve as a clinical predictive marker of taxol efficacy as well as a new drug target for future anti-cancer therapy.

pharmacology and toxicology↗