학술논문
PKC[alpha] is required for Akt-mTORC1 activation in non-small cell lung carcinoma (NSCLC) with EGFR mutation
Document Type
Academic Journal
Author
Source
Oncogene. November 2019, Vol. 38 Issue 48, p7311, 18 p.
Subject
Language
English
ISSN
0950-9232
Abstract
Author(s): Mohamed F. Salama [sup.1] [sup.2] [sup.3], Mengling Liu [sup.1] [sup.2] [sup.4], Christopher J. Clarke [sup.1] [sup.2], Mel Pilar Espaillat [sup.1] [sup.2], John D. Haley [sup.5], Ting Jin [sup.6], Daifeng [...]
Mutational activation of the epidermal growth factor receptor (EGFR) is a major player in the pathogenesis of non-small cell lung cancer (NSCLC). NSCLC patients with constitutively active EGFR mutations eventually develop drug resistance against EGFR tyrosine-kinase inhibitors; therefore, better understandings of key components of mutant EGFR (mtEGFR) signaling are required. Here, we initially observed aberrantly high expression of protein kinase C[alpha] (PKC[alpha]) in lung adenocarcinomas, especially those with EGFR mutations, and proceeded to examine the role of PKC[alpha] in the regulation of the signaling pathways downstream of mtEGFR. The results showed that NSCLC cell lines with constitutively active EGFR mutations tend to have very or moderately high PKC[alpha] levels. Furthermore, PKC[alpha] was constitutively activated in HCC827 and H4006 cells which have an EGFR deletion mutation in exon 19. Interestingly, mtEGFR was not required for the induction of PKC[alpha] at protein and message levels suggesting that the increased levels of PKC[alpha] are due to independent selection. On the other hand, mtEGFR activity was required for robust activation of PKC[alpha]. Loss of functions studies revealed that the NSCLC cells rely heavily on PKC[alpha] for the activation of the mTORC1 signaling pathway. Unexpectedly, the results demonstrated that PKC[alpha] was required for activation of Akt upstream of mTOR but only in cells with the mtEGFR and with the increased expression of PKC[alpha]. Functionally, inhibition of PKC[alpha] in HCC827 led to caspase-3-dependent apoptosis and a significant decrease in cell survival in response to cellular stress induced by serum starvation. In summary, the results identified important roles of PKC[alpha] in regulating mTORC1 activity in lung cancer cells, whereby a primary switching occurs from PKC[alpha]-independent to PKC[alpha]-dependent signaling in the presence of EGFR mutations. The results present PKC[alpha] as a potential synergistic target of personalized treatment for NSCLC with constitutively active mutant forms of EGFR and constitutively active PKC[alpha].
Mutational activation of the epidermal growth factor receptor (EGFR) is a major player in the pathogenesis of non-small cell lung cancer (NSCLC). NSCLC patients with constitutively active EGFR mutations eventually develop drug resistance against EGFR tyrosine-kinase inhibitors; therefore, better understandings of key components of mutant EGFR (mtEGFR) signaling are required. Here, we initially observed aberrantly high expression of protein kinase C[alpha] (PKC[alpha]) in lung adenocarcinomas, especially those with EGFR mutations, and proceeded to examine the role of PKC[alpha] in the regulation of the signaling pathways downstream of mtEGFR. The results showed that NSCLC cell lines with constitutively active EGFR mutations tend to have very or moderately high PKC[alpha] levels. Furthermore, PKC[alpha] was constitutively activated in HCC827 and H4006 cells which have an EGFR deletion mutation in exon 19. Interestingly, mtEGFR was not required for the induction of PKC[alpha] at protein and message levels suggesting that the increased levels of PKC[alpha] are due to independent selection. On the other hand, mtEGFR activity was required for robust activation of PKC[alpha]. Loss of functions studies revealed that the NSCLC cells rely heavily on PKC[alpha] for the activation of the mTORC1 signaling pathway. Unexpectedly, the results demonstrated that PKC[alpha] was required for activation of Akt upstream of mTOR but only in cells with the mtEGFR and with the increased expression of PKC[alpha]. Functionally, inhibition of PKC[alpha] in HCC827 led to caspase-3-dependent apoptosis and a significant decrease in cell survival in response to cellular stress induced by serum starvation. In summary, the results identified important roles of PKC[alpha] in regulating mTORC1 activity in lung cancer cells, whereby a primary switching occurs from PKC[alpha]-independent to PKC[alpha]-dependent signaling in the presence of EGFR mutations. The results present PKC[alpha] as a potential synergistic target of personalized treatment for NSCLC with constitutively active mutant forms of EGFR and constitutively active PKC[alpha].