Sensitization of transformed rat fibroblasts to killing by parvovirus minute virus of mice correlates with an increase in viral gene expression

Abstract

Cultures of established rat fibroblasts transformed by the avian erythroblastosis virus were more susceptible to the cytopathic effect of the autonomous parvovirus minute virus of mice, prototype strain (MVMp), than were their untransformed homologs. This effect could be ascribed to the presence of a greater fraction of cells that were sensitive to the killing action of MVMp in transformed cultures than in their normal parents. Yet, transformed and normal lines were similarly efficient in virus uptake, DNA amplification, and capsid protein synthesis. In contrast, transformants accumulated 2.5to 3-fold greater amounts of all three major MVM mRNA species and nonstructural protein than did their normal progenitors. Thus, in this system transformation-associated sensitization of cells to MVMp appears to correlate primarily with an increase in their capacity for the expression of the viral transcription unit which encodes nonstructural proteins and is controlled by the P4 promoter. Consistently, a reporter gene was expressed at a higher level by transformed versus normal cultures, when placed under the control of the MVM P4 promoter. As infectious MVMp was produced in larger amounts by transformed cultures, a late step of the parvoviral cycle, such as synthesis, encapsidation of progeny DNA, or both, was also stimulated in the transformed cells.

Influence of adeno-associated virus on adherence and growth properties of normal cells

“…This may mean that conditions required for pro- (2a) that codes for the viral regulatory proteins. Growth arrest and cell cycle perturbation by influence of the parvoviral regulatory proteins would be in agreement with data that ascribe cell killing to their action (11,13,14,37). However, we have thus far been unable to demonstrate Rep protein by either Western immunoblot or immunofluorescence (2a).…”

“…It appears, however, that the nonstructural proteins play an important role. They interfere with a multitude of cellular processes such as gene expression from heterologous promoters (23,28), neoplastic transformation (19,20), and stable transformation of cells by exogenous DNA (23,25,27) and may be correlated to killing of transformed cells (11,13,14,37). AAV oncosuppressive effects have been observed mainly by interference of AAV with the oncogenicity of helper viruses (reviewed in reference 29).…”

Investigation of the sensitivities of distinct gastric cancer cells to parvovirus H‐1 induced cytotoxicity

“…The molecular approach to treatment, such as cancer gene therapy, promises a meaningful method of preventing and treating gastric cancer. Parvovirus H‐1 exerts preferential killing and suppression of certain transformed and tumor cells, 5,6 making its a promising vector for anticancer gene therapies 7–9 . However, different types of tumor cells may exhibit differential susceptibilities to H‐1 virus induced cytotoxicity.…”

“…In general, fast‐growing and poorly differentiated tumor cells are sensitive to parvovirus‐induced lytic effects. In most systems studied so far, sensitization of the host cells to parvovirus‐induced killing has been shown to correlate with an increase in their capacity for viral DNA replication and gene expression 5,10 . The effect of this stimulation of the viral life‐cycle is to enrich the infected cells for viral NS proteins, in particular the NS1 protein whose toxicity may contribute to the oncolytic process.…”

ras oncogene-dependent activation of the P4 promoter of minute virus of mice through a proximal P4 element interacting with the Ets family of transcription factors

“…The above-mentioned dependence of the outcome of parvovirus infections on the physiological state of host cells is exemplified by the oncotropism of these agents and may underlie their ability to prevent the appearance or cause the regression of a variety of tumors (for a review, see reference 50). In addition, oncogenic transformation of a number of host cells (fibroblasts and epithelial cells of human or rodent origin) is accompanied by an increase in their sensitivity to the killing effect of MVMp (12,51,57), raising the possibility that the antitumor activity of this agent in vivo (28) involves an oncolytic component. In this respect, it is worth mentioning that NS-1 not only is involved in parvovirus DNA replication and gene expression (16,20,23,52,56) but also has been shown to be cytotoxic (9,10,39).…”