Abera, M., Sordella, R., Kazanietz, M. (April 2013) PKC alpha is implicated in epithelial to mesenchymal transition and erlotinib resistance in non-small cell lung carcinoma cells. Cancer Research, 73 (8 (Sup). p. 5261. ISSN 0008-5472
Abstract
Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) play important roles in the pathogenesis of non-small-cell lung cancer (NSCLC). For patients with EGFR activating mutations, EGFR tyrosine kinase inhibitors (TKIs) are given as a primary therapy. However, the majority of these patients eventually develop resistance to TKIs. To address a potential role of PKC isozymes in the resistance to TKIs, we used an isogenic model: the NSCLC H1650 cell line and its erlotinib-resistance derivative H1650-M3. H1650-M3 cells display a mesenchymal-like morphology driven by TGF-β signaling (PNAS 107:15535-15540, 2010). Comparison of the expression of PKC isozymes by Western blot between parental and erlotinib-resistant H1650 cells revealed that the M3 derivative displays remarkably high levels of PKCα and reduced levels of PKC{delta}. qPCR analysis established that PKCα mRNA levels in H1650-M3 cells are ~ 40-fold higher than in parental cells. In order to investigate a potential involvement of PKCα in TKI resistance we used RNAi. Upon PKCα depletion H1650-M3 cells display a morphology that is consistent with the epithelial phenotype. Moreover, depletion of PKCα from H1650-M3 cells led to significant changes in the expression of EMT markers. Indeed, mRNA levels of vimentin, Zeb2, SNAIL and TWIST were reduced by more than 50 % in erlotinib-resistant cells when PKCα expression was silenced. Analysis of cell viability in response to erlotinib treatment showed that pretreatment with either the pan-PKC inhibitor GF 109203X or the cPKC inhibitor Gö6976 sensitized H1650-M3 to erlotinib. Furthermore, PKCα RNAi depletion markedly sensitized H1650 cells to the TKI. Therefore, PKCα up-regulation in erlotinib-resistant cells may play an important role in driving the resistance to the drug. Our results also highlight a potential role for PKCα in EMT in lung cancer cells.
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > drugs and therapies > chemotherapy organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell diseases & disorders > cancer > cancer types > lung cancer Publication Type > Meeting Abstract |
| CSHL Authors: | |
| Communities: | CSHL labs > Sordella lab |
| Depositing User: | Matt Covey |
| Date: | April 2013 |
| Date Deposited: | 11 Apr 2014 16:39 |
| Last Modified: | 12 Feb 2018 17:06 |
| URI: | https://repository.cshl.edu/id/eprint/29752 |
Actions (login required)
 |
Administrator's edit/view item |
