liu.seSök publikationer i DiVA
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Human leukemic cell lines express a truncated intracellular 160 kDa ERBB2 receptor
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

It has recently been demonstrated that ERBB specific tyrosine kinase inhibitors display antineoplastic activity in human leukemic cell devoid of functional ERBB receptors. The present study was undertaken in order to identify any putative target for these drugs. Flow cytometry experiments demonstrate the presence of an immunoreactive ERBB2 protein of intracellular localization and Western blot analysis visualized an ERBB2 protein of approximately 160 kDa. Exposing leukemia cells to tunicamycin did not alter the size of the truncated ERBB2 protein. The ERBB2 gene was alternative spliced with an absence of exon 5 containing the start codon for the full-length protein. In conclusion we demonstrate a nonglycosylated 160 kDa ERBB2-receptor protein with an alternative in-frame start codon in human leukemia cell lines.

Nyckelord [en]
Leukemia, ERBB2-receptor, variant, glycosylation, exon
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-75548OAI: oai:DiVA.org:liu-75548DiVA, id: diva2:508125
Tillgänglig från: 2012-03-07 Skapad: 2012-03-07 Senast uppdaterad: 2012-03-07Bibliografiskt granskad
Ingår i avhandling
1. Canertinib-induced leukemia cell death signaling: effects of a pan-ERBB inhibitor
Öppna denna publikation i ny flik eller fönster >>Canertinib-induced leukemia cell death signaling: effects of a pan-ERBB inhibitor
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Acute myelogenous leukemia (AML) is the most common acute leukemia affecting adults, the second most frequent leukemia in children, and remains one of the most difficult to cure. Despite a substantial progress in understanding the pathogenesis of AML, general and rather unspecific cytostatic drugs such as cytarabine and anthracyclins still make up the cornerstones of therapy. Problems with these protocols include toxicity and the occurrence of resistance to the drugs in many patients. In order to extend the treatment options and ultimately improve survival for patients with leukemia it is imperative to increase the therapeutic arsenal with effective targeted therapies, preferentially with different mechanisms of action. AML due to a substantial heterogeneity between patients and within the clones in the same patient, as well as T-cell malignancies, are particularly difficult to treat since it is almost impossible to eradicate all leukemic stem cells using chemotherapy, thus there is a need to find more specific and effective treatments. Canertinib is a novel tyrosine kinase inhibitor developed for the treatment of certain solid cancers and has been designed to specifically inhibit all member of the ERBB-receptor family (ERBB1, ERBB2, ERBB3 and ERBB4). However, there are indications that canertinib has a broader specificity and it has not been tested on patients with leukemia.

The aim of this thesis was to investigate the anti-proliferative and pro-apoptotic effects and mechanisms of canertinib in human leukemia cells, and more specifically to clarify the cell death pathway and potential targets for the drug in these cells.

Canertinib treatment of leukemia cell lines resulted in an ERBB-independent induction of the intrinsic apoptotic pathway and activation of caspase-10, -9, and -8 as a consequence of Akt and Erk inhibition. In the human T-cell leukemia cell line Jurkat, the effects were associated to dephosphorylation of the lymphocyte-specific proteins, Lck and Zap-70. However, as full-length ERBB receptors were absent in leukemic cell lines other possible targets for canertinib were investigated. The FLT3 receptor, frequently mutated in AML, was discovered as a target since canertinib inhibited FLT3 autophosphorylation and kinase activity as well as downstream targets. The search for other possible proteins that might account for the effect exerted by canertinib, lead to the discovery of a truncated form of ERBB2 in human leukemic cells.

In conclusion, canertinib display promising anti-tumor effects on malignant hematopoietic cells and might be used in future studies in combination with conventional chemotherapy or other targeted therapies in the treatment of leukemia.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2012. s. 76
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1289
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-75549 (URN)978-91-7519-983-2 (ISBN)
Disputation
2012-03-30, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2012-03-07 Skapad: 2012-03-07 Senast uppdaterad: 2019-12-10Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Personposter BETA

Trinks, CeciliaHolmlund, BirgittaJönsson, Jan-IngvarWalz, Thomas M.

Sök vidare i DiVA

Av författaren/redaktören
Trinks, CeciliaHolmlund, BirgittaJönsson, Jan-IngvarWalz, Thomas M.
Av organisationen
CellbiologiHälsouniversitetetOnkologiExperimentell hematologiOnkologiska kliniken US
Medicin och hälsovetenskap

Sök vidare utanför DiVA

GoogleGoogle Scholar

urn-nbn

Altmetricpoäng

urn-nbn
Totalt: 108 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf