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Loss of RASSF2 Enhances Tumorigencity of Lung Cancer Cells and Confers Resistance to Chemotherapy.

Clark J, Freeman J, Donninger H - Mol Biol Int (2012)

Bottom Line: RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation.In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector.Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes.

View Article: PubMed Central - PubMed

Affiliation: Molecular Targets Program, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA.

ABSTRACT
RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation. Inactivation of RASSF2 enhances K-Ras-mediated transformation and overexpression of RASSF2 suppresses tumor cell growth. In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector. We adopted an RNAi approach to determine the effects of inactivation of RASSF2 on the transformed phenotype of lung cancer cells containing an oncogenic K-Ras. Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes. This enhanced transformed phenotype of the cells correlated with increased levels of activated AKT, indicating that RASSF2 can modulate Ras signaling pathways. Loss of RASSF2 expression also confers resistance to taxol and cisplatin, two frontline therapeutics for the treatment of lung cancer. Thus we have shown that inactivation of RASSF2, a process that occurs frequently in primary tumors, enhances the transforming potential of activated K-Ras and our data suggests that RASSF2 may be a novel candidate for epigenetic-based therapy in lung cancer.

No MeSH data available.


Related in: MedlinePlus

Inactivation of RASSF2 causes morphology changes. H441 cells stably expressing RASSF2 shRNA constructs and a control shRNA were viewed and photographed using phase contrast at 100x magnification.
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fig3: Inactivation of RASSF2 causes morphology changes. H441 cells stably expressing RASSF2 shRNA constructs and a control shRNA were viewed and photographed using phase contrast at 100x magnification.

Mentions: Overexpression of RASSF2 has been shown to induce cell morphological changes [24], and we have confirmed this in our RASSF2 knockdown cells. Loss of RASSF2 expression resulted in a dramatic alteration in cell morphology. The control H441 cells had a flattened morphology and grew in a monolayer, whereas the cells stably expressing the RASSF2 shRNA constructs became more rounded, piled up on each other, and were more refractile, consistent with a more aggressive and transformed phenotype (Figure 3).


Loss of RASSF2 Enhances Tumorigencity of Lung Cancer Cells and Confers Resistance to Chemotherapy.

Clark J, Freeman J, Donninger H - Mol Biol Int (2012)

Inactivation of RASSF2 causes morphology changes. H441 cells stably expressing RASSF2 shRNA constructs and a control shRNA were viewed and photographed using phase contrast at 100x magnification.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368207&req=5

fig3: Inactivation of RASSF2 causes morphology changes. H441 cells stably expressing RASSF2 shRNA constructs and a control shRNA were viewed and photographed using phase contrast at 100x magnification.
Mentions: Overexpression of RASSF2 has been shown to induce cell morphological changes [24], and we have confirmed this in our RASSF2 knockdown cells. Loss of RASSF2 expression resulted in a dramatic alteration in cell morphology. The control H441 cells had a flattened morphology and grew in a monolayer, whereas the cells stably expressing the RASSF2 shRNA constructs became more rounded, piled up on each other, and were more refractile, consistent with a more aggressive and transformed phenotype (Figure 3).

Bottom Line: RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation.In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector.Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes.

View Article: PubMed Central - PubMed

Affiliation: Molecular Targets Program, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, 505 S. Hancock Street, Louisville, KY 40202, USA.

ABSTRACT
RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation. Inactivation of RASSF2 enhances K-Ras-mediated transformation and overexpression of RASSF2 suppresses tumor cell growth. In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector. We adopted an RNAi approach to determine the effects of inactivation of RASSF2 on the transformed phenotype of lung cancer cells containing an oncogenic K-Ras. Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes. This enhanced transformed phenotype of the cells correlated with increased levels of activated AKT, indicating that RASSF2 can modulate Ras signaling pathways. Loss of RASSF2 expression also confers resistance to taxol and cisplatin, two frontline therapeutics for the treatment of lung cancer. Thus we have shown that inactivation of RASSF2, a process that occurs frequently in primary tumors, enhances the transforming potential of activated K-Ras and our data suggests that RASSF2 may be a novel candidate for epigenetic-based therapy in lung cancer.

No MeSH data available.


Related in: MedlinePlus