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Chronic exposure to cigarette smoke leads to activation of p21 (RAC1)-activated kinase 6 (PAK6) in non-small cell lung cancer cells

Raja, Remya and Sahasrabuddhe, Nandini A and Radhakrishnan, Aneesha and Syed, Nazia and Solanki, Hitendra S and Puttamallesh, Vinuth N and Balaji, Sai A and Nanjappa, Vishalakshi and Datta, Keshava K and Babu, Niraj and Renuse, Santosh and Patil, Arun H and Izumchenko, Evgeny and Prasad, Keshava TS and Chang, Xiaofei and Rangarajan, Annapoorni and Sidransky, David and Pandey, Akhilesh and Gowda, Harsha and Chatterjee, Aditi (2016) Chronic exposure to cigarette smoke leads to activation of p21 (RAC1)-activated kinase 6 (PAK6) in non-small cell lung cancer cells. In: ONCOTARGET, 7 (38). pp. 61229-61245.

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Official URL: http://dx.doi.org/10.18632/oncotarget.11310

Abstract

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.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the IMPACT JOURNALS LLC, 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Depositing User: Id for Latest eprints
Date Deposited: 07 Dec 2016 06:00
Last Modified: 07 Dec 2016 06:00
URI: http://eprints.iisc.ac.in/id/eprint/55556

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