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; Samant,Charudatt; Bokare,Anand; Verma,Mahip; Nandakumar,Krishnadas; 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
View Affiliations

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.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar
2	Meador CB and Hata AN: Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights. Pharmacol Ther. 210(107522)2020.PubMed/NCBI View Article : Google Scholar
3	Wang M, Herbst RS and Boshoff C: Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 27:1345–1356. 2021.PubMed/NCBI View Article : Google Scholar
4	Travis WD, Brambilla E, Burke AP, Marx A and Nicholson AG: Introduction to The 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J Thorac Oncol. 10:1240–1242. 2015.PubMed/NCBI View Article : Google Scholar
5	Scheffler M, Bos M, Gardizi M, König K, Michels S, Fassunke J, Heydt C, Künstlinger H, Ihle M, Ueckeroth F, et al: PIK3CA mutations in non-small cell lung cancer (NSCLC): Genetic heterogeneity, prognostic impact and incidence of prior malignancies. Oncotarget. 20:1315–1326. 2015.PubMed/NCBI View Article : Google Scholar
6	Zhou X, Wang X, Zhu H, Gu G, Zhan Y, Liu C and Sun G: PI3K inhibition sensitizes EGFR wild-type NSCLC cell lines to erlotinib chemotherapy. Exp Ther Med. 21(9)2021.PubMed/NCBI View Article : Google Scholar
7	Hanker AB, Kaklamani V and Arteaga CL: Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors. Cancer Discov. 9:482–491. 2019.PubMed/NCBI View Article : Google Scholar
8	Basnet R, Gong GQ, Li C and Wang MW: Serum and glucocorticoid inducible protein kinases (SGKs): A potential target for cancer intervention. Acta Pharm Sin B. 8:767–771. 2018.PubMed/NCBI View Article : Google Scholar
9	Talarico C, Dattilo V, D'Antona L, Menniti M, Bianco C, Ortuso F, Alcaro S, Schenone S, Perrotti N and Amato R: SGK1, the new player in the game of resistance: Chemo-radio molecular target and strategy for inhibition. Cell Physiol Biochem. 39:1863–1876. 2016.PubMed/NCBI View Article : Google Scholar
10	Zhang Z, Xu Q, Song C, Mi B, Zhang H, Kang H, Liu H, Sun Y, Wang J, Lei Z, et al: Serum- and glucocorticoid-inducible kinase 1 is essential for osteoclastogenesis and promotes breast cancer bone metastasis. Mol Cancer Ther. 19:650–660. 2020.PubMed/NCBI View Article : Google Scholar
11	Lee LYW, Woolley C, Starkey T, Biswas S, Mirshahi T, Bardella C, Segditsas S, Irshad S and Tomlinson I: Serum- and glucocorticoid-induced kinase Sgk1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis. Clin Cancer Res. 25:629–640. 2019.PubMed/NCBI View Article : Google Scholar
12	Toska E, Castel P, Chhangawala S, Arruabarrena-Aristorena A, Chan C, Hristidis VC, Cocco E, Sallaku M, Xu G, Park J, et al: PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression. Cell Rep. 27:294–306.e5. 2019.PubMed/NCBI View Article : Google Scholar
13	Castel P, Ellis H, Bago R, Toska E, Razavi P, Carmona FJ, Kannan S, Verma CS, Dickler M, Chandarlapaty S, et al: PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kα inhibition. Cancer Cell. 30:229–242. 2016.PubMed/NCBI View Article : Google Scholar
14	Parra ER, Villalobos P, Mino B and Rodriguez-Canales J: Comparison of different antibody clones for immunohistochemistry detection of programmed cell death ligand 1 (PD-L1) on non-small cell lung carcinoma. Appl Immunohistochem Mol Morphol. 26:83–93. 2018.PubMed/NCBI View Article : Google Scholar
15	Juneja VR, McGuire KA, Manguso RT, LaFleur MW, Collins N, Haining WN, Freeman GJ and Sharpe AH: PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med. 214:895–904. 2017.PubMed/NCBI View Article : Google Scholar
16	Dantoing E, Piton N, Salaün M, Thiberville L and Guisier F: Anti-PD1/PD-L1 immunotherapy for non-small cell lung cancer with actionable oncogenic driver mutations. Int J Mol Sci. 22(6288)2021.PubMed/NCBI View Article : Google Scholar
17	Adorisio S, Cannarile L, Delfino DV and Ayroldi E: Glucocorticoid and PD-1 cross-talk: Does the immune system become confused? Cells. 10(2333)2021.PubMed/NCBI View Article : Google Scholar
18	Yang L, Huang F, Mei J, Wang X, Zhang Q, Wang H, Xi M and You Z: Posttranscriptional control of PD-L1 expression by 17β-estradiol via PI3K/Akt signaling pathway in ERα-positive cancer cell lines. Int J Gynecol Cancer. 27:196–205. 2017.PubMed/NCBI View Article : Google Scholar
19	Hydbring P, Malumbres M and Sicinski P: Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol. 17:280–292. 2016.PubMed/NCBI View Article : Google Scholar
20	McCubrey JA, Steelman LS, Franklin RA, Abrams SL, Chappell WH, Wong EWT, Lehmann BD, Terrian DM, Basecke J, Stivala F, et al: Targeting the RAF/MEK/ERK, PI3K/AKT and p53 pathways in hematopoietic drug resistance. Adv Enzyme Regul. 47:64–103. 2007.PubMed/NCBI View Article : Google Scholar
21	Won M, Park KA, Byun HS, Kim YR, Choi BL, Hong JH, Park J, Seok JH, Lee YH, Cho CH, et al: Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: Implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration. J Hepatol. 51:67–76. 2009.PubMed/NCBI View Article : Google Scholar
22	Tenbaum SP, Ordóñez-Morán P, Puig I, Chicote I, Arqués O, Landolfi S, Fernández Y, Herance JR, Gispert JD, Mendizabal L, et al: β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 18:892–901. 2012.PubMed/NCBI View Article : Google Scholar
23	Jiang L, Zhang J, Xu Y, Xu H and Wang M: Treating non-small cell lung cancer by targeting the PI3K signaling pathway. Chin Med J (Engl). 135:1272–1284. 2022.PubMed/NCBI View Article : Google Scholar
24	Mishra R, Patel H, Alanazi S, Kilroy MK and Garrett JT: PI3K inhibitors in cancer: Clinical implications and adverse effects. Int J Mol Sci. 22(3464)2021.PubMed/NCBI View Article : Google Scholar
25	Sherk AB, Frigo DE, Schnackenberg CG, Bray JD, Laping NJ, Trizna W, Hammond M, Patterson JR, Thompson SK, Kazmin D, et al: Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic. Cancer Res. 68:7475–7483. 2008.PubMed/NCBI View Article : Google Scholar
26	Tolcher AW, Peng W and Calvo E: Rational approaches for combination therapy strategies targeting the MAP kinase pathway in solid tumors. Mol Cancer Ther. 17:3–16. 2018.PubMed/NCBI View Article : Google Scholar