Abstract
Hypoxia in solid tumors is associated with the development of chemoresistance. Although many studies have focused on the effect of hypoxia on drug-induced apoptosis, the effect of nonapoptotic pathways on hypoxia-induced drug resistance has not been previously investigated. Here, we determined the effects of hypoxia on multiple forms of drug-induced death in human MDA-MB-231 breast carcinoma cells. Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents, including anthracyclines (daunorubicin and doxorubicin), epipodophyllotoxins (etoposide), and anthracenediones (mitoxantrone). Results revealed a high degree of heterogeneity in nuclear and cytoplasmic alterations in response to acute drug exposure; however, the majority of exposed cells displayed morphologic and biochemical changes consistent with drug-induced senescence. Hypoxia decreased only the proportion of cells in the senescent population, whereas the small proportion of cells exhibiting features of apoptosis or mitotic catastrophe were unaffected. Similar results were obtained with human HCT116 colon carcinoma cells, indicating that the protective effect of hypoxia on drug-induced senescence is not unique to MDA-MB-231 cells. Treatment of MDA-MB-231 cells with small interfering RNA targeting the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), a key regulator of cellular adaptations to hypoxia, prevented hypoxia-induced resistance. HIF-1alpha small interfering RNA also selectively abolished the hypoxia-induced changes in the senescent population, indicating that the increased survival was due to protection against drug-induced senescence. These results support a requirement for HIF-1 in the adaptations leading to drug resistance and reveal that decreased drug-induced senescence is also an important contributor to the development of hypoxia-induced resistance.
Highlights
Regions of hypoxia are present in many solid tumors due to an inadequate and poorly formed vasculature
Exposure of MDA-MB-231 cells to hypoxia (0.2% O2) for 24 h before drug treatment leads to significantly (P < 0.01) increased resistance to multiple anticancer drugs relative to cells maintained under standard culture conditions (20% O2; Fig. 1)
This study shows that hypoxia is able to increase tumor cell resistance to chemotherapeutic agents by preventing druginduced senescence independently of changes in the apoptotic fraction
Summary
Regions of hypoxia are present in many solid tumors due to an inadequate and poorly formed vasculature. Tumor cells often acquire the ability to adapt to hypoxia so that their internal oxygen homeostatic balance is maintained. Increasing evidence from experimental and clinical studies has revealed that tumor cell adaptations to hypoxia are closely linked to malignant progression and contribute to the development of resistance to ionizing radiation and chemotherapy (1 – 6). Cellular adaptations to hypoxia involve the coordinated expression of a large and diverse group of genes, many of which are transcriptionally regulated by hypoxia-inducible factor-1 HIF-1 is a transcription factor composed of HIF-1a and HIF-1h subunits. HIF-1h is constitutively expressed and control of HIF-1 function occurs primarily through the oxygen-dependent degradation of the a-subunit. HIF-1 binds to cisacting hypoxia response elements to induce the expression of target genes, several of which have physiologic relevance to malignant progression
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