The recognition that hypoxic microenvironments are important for the development of a more aggressive tumor phenotype stimulated investigations into the cellular response to hypoxia. It is now generally accepted that this results from an evolutionary process which leads to the selection of apoptosis-resistant tumor-cell subpopulations that may also possess the capability to promote the formation of new blood vessels ( 3). Tumor hypoxia has been linked to features of enhanced biological aggression, including resistance to anticancer treatments and increased metastatic potential ( 1, 2). Solid tumors frequently show areas of decreased oxygenation due to a morphologically abnormal and insufficient tumor vasculature whose development often does not keep pace with the growth of the neoplasm itself. Our results indicate that LSC can significantly contribute to the evaluation of in vitro drug effects particularly with respect to tumor hypoxia and the measurement of HIF-1α. Cell death due to geldanamycin occurs in association with mitosis, presumably through mitotic catastrophe. Both cell lines respond to geldanamycin with a G 2/M-phase arrest and a decrease in HIF-1α accumulation. Our analysis demonstrates that the cell lines react to hypoxia and drug treatment in a distinct way, with SiHa being more affected by low oxygen concentrations than is ME180, which was more sensitive to geldanamycin treatment. We describe here the simultaneous measurement of HIF-1α and cell cycle parameters by laser scanning cytometry (LSC) after exposure of two different human cervical carcinoma cell lines to hypoxia and geldanamycin. Hsp90 inhibitors like geldanamycin therefore have the potential to target tumor-cell survival by at least two mechanisms, compromising the accumulation of HIF-1α and cell proliferation. Heat shock protein 90 (Hsp90) is an essential protein that controls the activity, turnover, and trafficking of a variety of other proteins including HIF-1α and cell cycle regulators. The α-subunit of this factor is accumulated under hypoxia and rapidly degraded during re-oxygenation, rendering the reliable measurement of HIF-1α a difficult task. Tumor hypoxia has been linked to increased disease aggressiveness and poorer treatment outcomes, and the transcription factor hypoxia-inducible factor-1 (HIF-1) has been identified as the key molecule mediating the cellular response to hypoxic microenvironments.
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