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The role of GSTP1 in KRAS induced lung tumorigenesis

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The role of GSTP1 in KRAS induced lung tumorigenesis

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Samenvatting

Lung cancer is known for its aggressive and metastatic behavior. Non-Small Cell Lung cancer represent 85%
of patients diagnosed with lung caner. Despite novel advances in medical treatment and research the survival
rate did not change in the last three decades and is less than 5 years. Additionally it’s acknowledged that lung
cancer exhibits a substantially resistance against chemotherapeutic drugs. Therefor it’s vital to develop new
therapeutics that systematically work in combination with already existing chemotherapeutic drugs. 20-30% of
patients diagnosed with NSCLC harbor a KRAS mutation. Furthermore, it is implied that KRAS-induced
tumorigenesis impacts resistance to cancer treatment, cellular motility and invasiveness. Expression of
Glutathione S-transferase P1 (GSTP1) is significantly higher in tumor tissue of patients with NSCLC. Therefore a
better understanding of the contribution of GSTP1 in KRAS induced transformation, could lead to the
development of more effective therapeutic strategies in lung cancer treatment.
To determine the role of GSTP1 in KRASG12D induced tumorigenesis, we used in vitro as well in vivo models.
In our in vivo experiments we exposed human lung cancer cells with the GSTP1 inhibitor TLK-117 and analyzed
mRNA, protein and lactate production as well as total GST activity and protein s-glutathionylation (PSSG).
Pharmacological inhibition of GSTP1 by TLK-117 resulted in a significant decrease in lactate production and GST
activity in A549 cells. Furthermore we discovered that GSTP1 expression varied in different lung cancer cell lines.
TLK-117 significantly reduced cell migration in A549 and H292 cells and this appears to correlate with GSTP1
expression levels. In A549 cells TLK-117 reduced protein s-glutathionylation of PKM2, an important key regulator
of the Warburg Effect. We also developed a CCSP-rtTA/tetON-Cre/LSL-KRASG12D triple transgenic mouse.
Following initiation of the KRASG12D mutant using an adenovrius expressing Cre or doxycycline containing food
tumor burden was evaluated. Further, gene expression was analyzed by RT-qPCR and protein analysis by
Western blotting. In addition changes in lactate production and GST activity were determined. In KRASG12D
expressing mice gene expression of PKM2, HKII, HKIII, Glut2 and PDHKI increased and LDHA decreased.
Additionally an increased lactate production in these mice could be detected. Mice expressing KRASG12D that
were exposed to TLK-117 showed an slight decrease in GST activity and showed fewer tumor regions than
untreated mice.
Together, these findings demonstrate that GSTP1 plays an important role in KRASG12D induced
tumorigenesis, cancer cell migration, tumor progression and protein s-glutathionylation. It also implicates the
importance of GSTP1 in KRAS induced tumorigenesis and the relevance of TLK-117 as new important drug for
the treatment of NSCLC.

Toon meer
OrganisatieAvans Hogeschool
OpleidingBiologie en Medisch Laboratoriumonderzoek-Breda
AfdelingATGM Academie voor de technologie van Gezondheid en Milieu
Jaar2015
TypeBachelor
TaalEngels

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