Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells

Roberts, D. F.; Williams, Kaye J.; Cowen, Rachel L.; Baráthová, Monika; Eustace, Amanda; Brittain-Dissont, S.; Tilby, Michael J.; Pearson, D.G.; Ottley, Christopher J.; Stratford, Ian J.; Dive, Caroline

doi:10.1038/sj.bjc.6605311

Cited by 49 publications

(44 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Many of these HIF-1 inducible genes such as VEGF, Glut-1, MDR, and Bcl-2 directly or indirectly mediate chemoresistance 19 .Therefore, in a wide range of different tumor types, e.g. hepatocellular carcinoma, neuroblastoma, and lung cancer, inhibition of HIF-1α resensitizes cells to drug treatment in hypoxia and is then a valid target to reverse hypoxia-induced drug resistance 8,9,15,19,21,25,[27][28][29][30]56 . HIF-1α accumulation has been associated with shorter survival in patients with early stage cervical, breast, ovarian, endometrial, oropharyngeal squamous cell carcinoma, and oligodendroglioma.…”

Section: Hif-1 and Chemoresistancementioning

confidence: 99%

“…In this context, the most studied transcription factor is hypoxia-inducible factor-1 (HIF-1). HIF-1 is an important factor in the adaptation of cells to hypoxic environments, and significantly contributes to the aggressiveness and chemoresistance of number of different tumours 5,[7][8][9]15,19,21,[25][26][27][28][29][30] . However, these changes can be independent of HIF-1 (ref.…”

Section: Introduction -Hypoxia-induced Chemoresistancementioning

confidence: 99%

See 1 more Smart Citation

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Doktorova

Hraběta

Khalil

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

View full text Add to dashboard Cite

Background. The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Results. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. Conclusions. The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.

show abstract

Section: Hif-1 and Chemoresistancementioning

confidence: 99%

Section: Introduction -Hypoxia-induced Chemoresistancementioning

confidence: 99%

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Doktorova

Hraběta

Khalil

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

View full text Add to dashboard Cite

show abstract

Section: Cells Were More Sensitive Tomentioning

confidence: 99%

“…We have previously shown that hypoxic regions of HCT116 spheroids were less prone to apoptosis induced by the conventional cytotoxic agent oxaliplatin when compared with normoxic regions (24). Expression of a dominant negative (DN) HIF-1 prevents upregulation of the glucose transporter GLUT-1 in hypoxic regions of HCT116 spheroids (24). GLUT-1 and HIF1-α colocalized in these spheroids ( Figure 3A).The same 3D culture model was used here to investigate fur- ther the hypoxic sensitization to ABT-737, where CC3 was used to report apoptosis and GLUT-1 was used to report hypoxia.…”

Section: Cells Were More Sensitive Tomentioning

confidence: 99%

Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1

Harrison

Micha²,

Brandenburg³

et al. 2011

J. Clin. Invest.

View full text Add to dashboard Cite

Solid tumors contain hypoxic regions in which cancer cells are often resistant to chemotherapy-induced apoptotic cell death. Therapeutic strategies that specifically target hypoxic cells and promote apoptosis are particularly appealing, as few normal tissues experience hypoxia. We have found that the compound ABT-737, a Bcl-2 homology domain 3 (BH-3) mimetic, promotes apoptotic cell death in human colorectal carcinoma and small cell lung cancer cell lines exposed to hypoxia. This hypoxic induction of apoptosis was mediated through downregulation of myeloid cell leukemia sequence 1 (Mcl-1), a Bcl-2 family protein that serves as a biomarker for ABT-737 resistance. Downregulation of Mcl-1 in hypoxia was independent of hypoxia-inducible factor 1 (HIF-1) activity and was consistent with decreased global protein translation. In addition, ABT-737 induced apoptosis deep within tumor spheroids, consistent with an optimal hypoxic oxygen tension being necessary to promote ABT-737-induced cell death. Tumor xenografts in ABT-737-treated mice also displayed significantly more apoptotic cells within hypoxic regions relative to normoxic regions. Synergies between ABT-737 and other cytotoxic drugs were maintained in hypoxia, suggesting that this drug may be useful in combination with chemotherapeutic agents. Taken together, these findings suggest that Mcl-1-sparing BH-3 mimetics may induce apoptosis in hypoxic tumor cells that are resistant to other chemotherapeutic agents and may have a role in combinatorial chemotherapeutic regimens for treatment of solid tumors.

show abstract

“…Hypoxia in tumors is important clinically, because expression of Hif1α (5,6) and Hif2α (7) proteins is correlated with poorer prognosis. Hif1α expression is also associated with resistance to fluorouracil (5-FU) (8) and oxaliplatin (9).…”

mentioning

confidence: 99%

Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells

Yeung

Gandhi

Bodmer

2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hypoxia is an important regulator of normal and cancer stem cell (CSC) differentiation. Colorectal CSCs from SW1222, LS180, and CCK81 colorectal cancer-derived cell lines are able to differentiate into complex 3D lumen-containing structures in normoxia, whereas in hypoxia, they form undifferentiated dense colonies that have reduced expression of the enterocyte differentiation marker CDX1, lack goblet cell formation, and have increased expression of BMI1 and activated Notch1. Hypoxia increases the clonogenicity of CSCs, which is cumulative as each round of hypoxia enriches for more CSCs. The hypoxic phenotype is reversible, because cells from hypoxic-dense colonies are able to reform differentiated structures when regrown in normoxia. We show that CDX1 is able to stimulate the generation of lumens even in hypoxia and has a negative feedback on BMI1 expression. Knockdown of CDX1 reduces lumen formation but does not affect goblet cell formation, suggesting that enterocytes and goblet cells form from different progenitor cells. Notch inhibition by dibenzazepine (DBZ) allowed CSCs to form goblet cells in both normoxia and hypoxia. Finally, we show that Hif1α, but not CA9, is an important mediator of the effects of hypoxia on the clonogenicity and differentiation of CSCs. In summary, hypoxia maintains the stem-like phenotype of colorectal cell linederived CSCs and prevents differentiation of enterocytes and goblet cells by regulating CDX1 and Notch1, suggesting that this regulation is an important component of how hypoxia controls the switch between stemness and differentiation in CSCs.

show abstract

Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells

Cited by 49 publications

References 20 publications

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1

Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells

Contact Info

Product

Resources

About