Inhibition of SGK1 potentiates the anticancer activity of PI3K inhibitor in NSCLC cells through modulation of mTORC1, p‑ERK and β‑catenin signaling

Kale,Ramesh; Kale,Ramesh; Samant,Charudatt; Samant,Charudatt; Bokare,Anand; Bokare,Anand; Verma,Mahip; Verma,Mahip; Nandakumar,Krishnadas; Nandakumar,Krishnadas; Bhonde,Mandar; Bhonde,Mandar

doi:10.3892/br.2023.1676

Inhibition of SGK1 potentiates the anticancer activity of PI3K inhibitor in NSCLC cells through modulation of mTORC1, p‑ERK and β‑catenin signaling

Authors:
- Ramesh Kale
- Charudatt Samant
- Anand Bokare
- Mahip Verma
- Krishnadas Nandakumar
- Mandar Bhonde
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Affiliations: Department of Pharmacology, Novel Drug Discovery and Development, Lupin Limited, Pune, Maharashtra 412115, India, Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
Published online on: October 13, 2023 https://doi.org/10.3892/br.2023.1676
Article Number: 94
Copyright: © Kale et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non‑small cell lung cancer (NSCLC) is one of the deadliest types of cancer with poor prognosis, accounting for 85% of all lung cancer cases. The phosphoinositide 3‑kinase (PI3K) signaling pathway is most frequently altered in NSCLC; nonetheless, targeting this pathway yields limited success primarily because of drug‑induced resistance. PI3K‑independent activation of serum and glucocorticoid‑induced kinase 1 (SGK1) is responsible for development of resistance to PI3K/AKT inhibitors in breast cancer. The present study investigated potential of inhibiting SGK1 activity for the potentiation of PI3K inhibitor activity in NSCLC cell lines using in vitro anti‑proliferation assays, protein expression profiling using western blotting and cell cycle analysis. The findings revealed that combined inhibition of PI3K/AKT and SGK1 resulted in synergistic anticancer activity, with increased apoptosis, DNA damage and cell cycle arrest in G1 phase. Furthermore, high SGK1 protein expression in NSCLC cell lines was associated with increased resistance to PI3K inhibitors. Therefore, enhanced SGK1 expression may serve as a marker to predict therapeutic response to PI3K/AKT inhibitors. Profiling of downstream signaling proteins demonstrated that, at the molecular level SGK1‑mediated sensitization of NSCLC cell lines to PI3K inhibitors was achieved via inhibition of mTORC1 signaling. Increased sensitivity of NSCLC cell lines was also mediated by other oncogenic pathways, such as Ras/MEK/ERK and Wnt/β‑catenin signaling.

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