Inhibition of Nucleolar Function and Morphological Change by Adriamycin Associated with Heat Shock Protein 70 Accumulation

Abstract

Adriamycin (ADR) has been considered to target mainly DNA metabolism in the nucleus. Recently, we observed the nuclear translocation of heat shock protein 70 (HSP70) after ADR treatment. We examined which intranuclear changes might be related to this alteration of HSP70 localization. We found considerable alternations in the nucleolar morphology and function in ADR‐treated tumor cells, i.e., a ring‐shaped segregation of granular components of almost all nucleoli and a dramatic reduction of nucleolar 45S ribosomal precursor RNA biosynthesis in HeLa cells exposed to 100 μM ADR for 2 h. Concomitantly with these changes, HSP70 was concentrated into the nucleoli, as in the case of heat shock treatment. These results indicate a novel anticancer effect of ADR via the suppression of cellular protein biosynthesis, in addition to its effect on DNA.

Evidence of p53-Dependent Cross-Talk between Ribosome Biogenesis and the Cell Cycle: Effects of Nucleolar Protein Bop1 on G1/S Transition

“…21,2001 p53-DEPENDENT EFFECTS OF Bop1 ON CELL CYCLE 4253 various disturbances in cellular metabolism, including various chemical inhibitors (1,10,30,56,70,71), reduced protein synthesis (21,44), and starvation (35,62). Hence, detection of anomalies in ribosome biogenesis could potentially provide integration of a variety of inputs indicating unfavorable or toxic environmental conditions.…”

“…One interesting feature of the nucleolar stress model is that it provides a possible mechanism for the antiproliferative effects of a diverse group of metabolic inhibitors, including many clinically important anticancer drugs, that strongly inhibit the rRNA synthesis and processing machinery (1,10,56,70,71). At present, the contribution of impaired RNA synthesis and processing to their action is poorly understood.…”

Low-energy-loss electron microscopy of doxorubicin in human breast cancer MCF-7 cells: Localization by color

“…Biochemical studies point to intercalation of DNA (Goto et al, 2001), complexation with and inhibition of topoisomeraseII (D'Arpa D' Arpa and Liu, 1989) or to oxidative DNA damage by DOX-induced radical formation (Mizutani et al, 2003). Structural studies have implicated various subcellular structures such as the plasma membrane (Arancia, 1988;Arancia et al, 1995), the nuclear membrane and chromatin (Altan et al, 1998), and the nucleolus (Merski et al, 1976(Merski et al, , 1978Unverferth et al, 1983;Cavanagh et al, 1987;Abe et al, 1996). In part the different results may be due to different actions of doxorubicin in different cells, even in variants of the same MCF-7 cell line (Gooch and Yee, 1999), but it is also clear that part of the quandaries arise from lack of sufficient spatial resolution when doxorubicin or its namesake adriamycin is observed in the light microscope, or from lack of chemical specificity when electron microscopic observations were made.…”

“…For example, in an in-depth study by fluorescence on the interaction between doxorubicin and various modifiers of subcellular organelles Altan et al (1998) state that the doxorubicin fluorescence observed in their MCF-7 cells may be accumulating ''in the nuclear envelope or binding to the adjacent euchromatin'', and that ''the high density of organelles throughout the cytoplasm makes it impossible to resolve adriamycin fluorescence selectively''. Alternatively, the presence of doxorubicin is only inferred when alterations in structure are seen by electron microscopy, such as the clear tracts in erythrocyte plasma membranes treated with doxorubicin (Arancia et al, 1995;Arancia, 1988), the clumping of chromatin (Unverferth et al, 1983), the ''clearing'' of nuclear areas in spinal ganglia (Cavanagh et al, 1987), and the ring-like segregations seen with nucleoli of lung, cardiac or HeLa cells exposed to doxorubicin (Merski et al, 1976;Abe et al, 1996).…”

Development and characterization of an in vitro model of colorectal adenocarcinoma with MDR phenotype

“…Ultrastructural studies showed the occurrence of doxorubicin nucleolar segregation in rat liver and heart cells [22], and Abe and coworkers found considerable alterations in the nucleolar morphology and function on Hela cells treated with doxorubicin. This treatment also induced a dramatic reduction of nucleolar 45S ribosomal precursor RNA biosynthesis [23]. Moreover, recent findings show that changes in nucleolar morphology is related to cellular activity, such as growth, proliferation, and cell cycle progression [24].…”