Abstract
Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
| Original language | English |
|---|---|
| Pages (from-to) | 1430-1436 |
| Number of pages | 7 |
| Journal | International Journal of Oncology |
| Volume | 45 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2014 |
| Externally published | Yes |
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Keywords
- ALK inhibitor
- EML4-ALK rearrangement
- Epithelial-mesenchymal transition
- Hypoxia
- Non-small cell lung cancer
ASJC Scopus subject areas
- Cancer Research
- Oncology
- Medicine(all)
Cite this
Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition. / Kogita, Akihiro; Togashi, Yosuke; Hayashi, Hidetoshi; Sogabe, Shunsuke; Terashima, Masato; De Velasco, Marco A.; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Takeyama, Yoshifumi; Okuno, Kiyotaka; Nakagawa, Kazuhiko; Nishio, Kazuto.
In: International Journal of Oncology, Vol. 45, No. 4, 2014, p. 1430-1436.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition
AU - Kogita, Akihiro
AU - Togashi, Yosuke
AU - Hayashi, Hidetoshi
AU - Sogabe, Shunsuke
AU - Terashima, Masato
AU - De Velasco, Marco A.
AU - Sakai, Kazuko
AU - Fujita, Yoshihiko
AU - Tomida, Shuta
AU - Takeyama, Yoshifumi
AU - Okuno, Kiyotaka
AU - Nakagawa, Kazuhiko
AU - Nishio, Kazuto
PY - 2014
Y1 - 2014
N2 - Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
AB - Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
KW - ALK inhibitor
KW - EML4-ALK rearrangement
KW - Epithelial-mesenchymal transition
KW - Hypoxia
KW - Non-small cell lung cancer
UR - http://www.scopus.com/inward/record.url?scp=84907462932&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907462932&partnerID=8YFLogxK
U2 - 10.3892/ijo.2014.2574
DO - 10.3892/ijo.2014.2574
M3 - Article
C2 - 25096400
AN - SCOPUS:84907462932
VL - 45
SP - 1430
EP - 1436
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 4
ER -