2011
DOI: 10.1172/jci44362
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Abstract: Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2)… Show more

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Cited by 87 publications
(97 citation statements)
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“…Several different mechanisms, such as downregulation of proapoptotic factors and upregulation of epithelial-mesenchymal transition (EMT), have been suggested for hypoxia-mediated drug resistance (10,38). More recently, it has been shown that downregulation of dual-specificity phosphatase 2 (DUSP2) leads to reduced sensitivity to MEK inhibitors in HeLa cells (11). In our current study, we demonstrated that the level of PHLPP expression regulates drug sensitivity in colon cancer cells and that downregulation of PHLPP contributes to hypoxiainduced chemoresistance.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Several different mechanisms, such as downregulation of proapoptotic factors and upregulation of epithelial-mesenchymal transition (EMT), have been suggested for hypoxia-mediated drug resistance (10,38). More recently, it has been shown that downregulation of dual-specificity phosphatase 2 (DUSP2) leads to reduced sensitivity to MEK inhibitors in HeLa cells (11). In our current study, we demonstrated that the level of PHLPP expression regulates drug sensitivity in colon cancer cells and that downregulation of PHLPP contributes to hypoxiainduced chemoresistance.…”
Section: Discussionmentioning
confidence: 99%
“…The inhibition of mTORC1-dependent protein translation has been suggested to affect cellular tolerance to hypoxia; however, it remains elusive how hypoxia-induced downregulation of translation contributes to tumor progression. Furthermore, cancer cells exposed to hypoxic conditions are notoriously known to be more resistant to apoptosis induced by radiation and chemotherapy drugs, and a variety of mechanisms have been suggested to affect the treatment sensitivity (9)(10)(11)(12). Thus, a better understanding of hypoxia-mediated chemoresistance is needed in order to treat cancer cells more effectively.…”
mentioning
confidence: 99%
“…2) that can explain the downregulation of DUSP2 and parallel elevation of ERK and HIF-1 activity in hypoxic cancer cells. It is, however, ambiguous the fact that hypoxic DUSP2 suppression was not observed in hepatoma cell lines and clinical samples of cancerous liver had similar levels of DUSP2 mRNA as those derived from normal tissue (Lin et al, 2011) suggesting limited and tissuespecific relevance of this mechanism.…”
Section: Erk Pathway and Hif-1αmentioning
confidence: 97%
“…Since excessive and prolonged activation of ERK or HIF-1 may lead to apoptosis (Cagnol et al, 2006;Carmeliet et al, 1998), this negative feedback may act to limit ERK and, consequently, HIF-1 activity to a threshold compatible with cell survival and proliferation under hypoxia. On the other hand, HIF-1 has been recently shown to inhibit DUSP2 transcription causing DUSP2 suppression and prolonged phosphorylation of ERK, which increased chemoresistance and malignancy in human cancer cells under hypoxia (Lin et al, 2011). This suggests the additional operation of a feedforward (or positive feedback) loop (also shown in Fig.…”
Section: Erk Pathway and Hif-1αmentioning
confidence: 98%
“…For examples, studies have shown that hypoxia is directly involved in the induction of genes coding for the ABC transporters (MDR1, MRP1 and LRP), responsible for HepG2 cells resistance toward 5-Fluorouracil (Comerford et al, 2002;Zhu et al, 2005). Moreover, a recent study has demonstrated that, by down-regulating the expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2), HIF-1 is involved in the resistance of HeLa and HCT116 cells to cisplatin, oxaliplatin, and paclitaxel (Lin et al, 2011). Hypoxia, by modulating expression of enzymes directly involved in metabolism of chemotherapeutic drugs, such as CYPs, could also limit the toxic effects of these drugs on cancer cells.…”
Section: Hif-1 and Hif-target Genes: Actors For Drug Resistancementioning
confidence: 99%