TY - JOUR
T1 - Chronic exposure to cigarette smoke leads to activation of p21 (RAC1)-activated kinase 6 (PAK6) in non-small cell lung cancer cells
AU - Raja, Remya
AU - Sahasrabuddhe, Nandini A.
AU - Radhakrishnan, Aneesha
AU - Syed, Nazia
AU - Solanki, Hitendra S.
AU - Puttamallesh, Vinuth N.
AU - Balaji, Sai A.
AU - Nanjappa, Vishalakshi
AU - Datta, Keshava K.
AU - Babu, Niraj
AU - Renuse, Santosh
AU - Patil, Arun H.
AU - Izumchenko, Evgeny
AU - Prasad, T. S.Keshava
AU - Chang, Xiaofei
AU - Rangarajan, Annapoorni
AU - Sidransky, David
AU - Pandey, Akhilesh
AU - Gowda, Harsha
AU - Chatterjee, Aditi
N1 - Funding Information:
We thank the Department of Biotechnology (DBT), Government of India for research support to the Institute of Bioinformatics (IOB), Bangalore. We thank the "Infosys Foundation" for research support to IOB. This work was supported by Department of Science and Technology (DST) grants (SERC/LS-439/2011 and SR/SO/HS/0208/2013). IOB is supported by DBT Program Support on Neuroproteomics and infrastructure for proteomic data analysis (BT/01/COE/08/05). This work was supported by NCI's Clinical Proteomic Tumor Analysis Consortium initiative (U24CA160036) and FAMRI-funded 072017_YCSA. RR is a recipient of Research Associateship from DBT. AR is a recipient of Senior Research Fellowship from Council of Scientific and Industrial Research (CSIR), Government of India. NS and KKD are recipients of Senior Research Fellowship from University Grants Commission (UGC), Government of India. We thank Dr. vani santosh National Institute of Mental Health and Neurological Sciences (NIMHANS), for scoring the immunohistochemistry results. We thank Dr. S. K. Shankar and Dr. Anita Mahadevan (NIMHANS), for providing access to the microscopy imaging facility.
PY - 2016
Y1 - 2016
N2 - Epidemiological data clearly establishes cigarette smoking as one of the major cause for lung cancer worldwide. Recently, targeted therapy has become one of the most preferred modes of treatment for cancer. Though certain targeted therapies such as anti-EGFR are in clinical practice, they have shown limited success in lung cancer patients who are smokers. This demands discovery of alternative drug targets through systematic investigation of cigarette smoke-induced signaling mechanisms. To study the signaling events activated in response to cigarette smoke, we carried out SILAC-based phosphoproteomic analysis of H358 lung cancer cells chronically exposed to cigarette smoke. We identified 1,812 phosphosites, of which 278 phosphosites were hyperphosphorylated (≥ 3-fold) in H358 cells chronically exposed to cigarette smoke. Our data revealed hyperphosphorylation of S560 within the conserved kinase domain of PAK6. Activation of PAK6 is associated with various processes in cancer including metastasis. Mechanistic studies revealed that inhibition of PAK6 led to reduction in cell proliferation, migration and invasion of the cigarette smoke treated cells. Further, siRNA mediated silencing of PAK6 resulted in decreased invasive abilities in a panel of non-small cell lung cancer (NSCLC) cells. Consistently, mice bearing tumor xenograft showed reduced tumor growth upon treatment with PF-3758309 (group II PAK inhibitor). Immunohistochemical analysis revealed overexpression of PAK6 in 66.6% (52/78) of NSCLC cases in tissue microarrays. Taken together, our study indicates that PAK6 is a promising novel therapeutic target for NSCLC, especially in smokers.
AB - Epidemiological data clearly establishes cigarette smoking as one of the major cause for lung cancer worldwide. Recently, targeted therapy has become one of the most preferred modes of treatment for cancer. Though certain targeted therapies such as anti-EGFR are in clinical practice, they have shown limited success in lung cancer patients who are smokers. This demands discovery of alternative drug targets through systematic investigation of cigarette smoke-induced signaling mechanisms. To study the signaling events activated in response to cigarette smoke, we carried out SILAC-based phosphoproteomic analysis of H358 lung cancer cells chronically exposed to cigarette smoke. We identified 1,812 phosphosites, of which 278 phosphosites were hyperphosphorylated (≥ 3-fold) in H358 cells chronically exposed to cigarette smoke. Our data revealed hyperphosphorylation of S560 within the conserved kinase domain of PAK6. Activation of PAK6 is associated with various processes in cancer including metastasis. Mechanistic studies revealed that inhibition of PAK6 led to reduction in cell proliferation, migration and invasion of the cigarette smoke treated cells. Further, siRNA mediated silencing of PAK6 resulted in decreased invasive abilities in a panel of non-small cell lung cancer (NSCLC) cells. Consistently, mice bearing tumor xenograft showed reduced tumor growth upon treatment with PF-3758309 (group II PAK inhibitor). Immunohistochemical analysis revealed overexpression of PAK6 in 66.6% (52/78) of NSCLC cases in tissue microarrays. Taken together, our study indicates that PAK6 is a promising novel therapeutic target for NSCLC, especially in smokers.
KW - Mass spectrometry
KW - NSCLC
KW - P21 (RAC1)-activated kinase 6
KW - Smoking
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U2 - 10.18632/oncotarget.11310
DO - 10.18632/oncotarget.11310
M3 - Article
C2 - 27542207
AN - SCOPUS:84992486276
SN - 1949-2553
VL - 7
SP - 61229
EP - 61245
JO - Oncotarget
JF - Oncotarget
IS - 38
ER -