Abstract
Lung cancer is one of the most prevalent causes of morbidity and mortality in both men and women across the globe. The disease has a quiet phenotype at first, which leads to chronic tumor development. Non-small cell lung cancer (NSCLC) is the most common kind of lung cancer, accounting for 85 percent of all lung malignancies. Autophagy has been described as an intracellular “recycle bin” where damaged proteins and molecules are degraded. Autophagy regulation is mainly dependent on signaling pathways such as phosphoinositide 3-kinases (PI3K), AKT, and the mammalian target of rapamycin (mTOR). In the context of NSCLC, studies on these signaling pathways are inconsistent, but our literature review suggests that the inhibition of mTOR, PI3K/AKT, and epidermal growth factor receptor signaling pathways by different medications can active autophagy and inhibit NSCLC progression. In conclusion, signaling pathways related to autophagy are effective therapeutic approaches for the treatment of NSCLC.
Similar content being viewed by others
Data availabilty
It is not applicable.
References
Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A et al (2021) Cancer statistics for the year 2020: an overview. Int J Cancer 149(4):778–789
Yazdani Z, Rafiei A, Golpour M, Zafari P, Moonesi M, Ghaffari S (2020) IL-35, a double-edged sword in cancer. J Cell Biochem 121(3):2064–2076
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics. CA: A Cancer J Clin 69(1):7–34
Mirzamoradi M, Hasani Nejhad F, Jamali R, Heidar Z, Bakhtiyari M (2020) Evaluation of the effect of antenatal betamethasone on neonatal respiratory morbidities in late preterm deliveries (34–37 weeks). J Matern Fetal Neonatal Med 33(15):2533–2540
Howlader N, NA KM, Miller D, Bishop K, Kosary C, Yu M, et al. (2017) SEER cancer statistics review, 1975–2014, based on November 2016 SEER data submission. National Cancer Institute: Bethesda, MD.
Bade BC, Cruz CSD (2020) Lung cancer 2020: epidemiology, etiology, and prevention. Clin Chest Med 41(1):1–24
Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD (2013) Epidemiology of lung cancer: diagnosis and management of lung cancer: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(5):e1S-e29S
Godtfredsen NS, Prescott E, Osler M (2005) Effect of smoking reduction on lung cancer risk. JAMA 294(12):1505–1510
Ost DE, Yeung S-CJ, Tanoue LT, Gould MK (2013) Clinical and organizational factors in the initial evaluation of patients with lung cancer: diagnosis and management of lung cancer: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(5):e121S – e141
Klionsky DJ (2008) Autophagy revisited: a conversation with Christian de Duve. Autophagy 4(6):740–743
Ávalos Y, Canales J, Bravo-Sagua R, Criollo A, Lavandero S, Quest AF (2014) Tumor suppression and promotion by autophagy. BioMed Res Int 2014:1–15
Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24(1):24–41
Chen N, Karantza-Wadsworth V (2009) Role and regulation of autophagy in cancer. Biochimica et Biophysica Acta (BBA)- Mol Cell Res 1793(9):1516–1523
Kaur J, Debnath J (2015) Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16(8):461–472
Galluzzi L, Vitale I, Abrams J, Alnemri E, Baehrecke E, Blagosklonny M et al (2012) Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012. Cell Death Differ 19(1):107–120
Barbosa MC, Grosso RA, Fader CM (2019) Hallmarks of aging: an autophagic perspective. Front Endocrinol 9:790
Rajabinejad M, Ranjbar S, Afshar Hezarkhani L, Salari F, Gorgin Karaji A, Rezaiemanesh A (2020) Regulatory T cells for amyotrophic lateral sclerosis/motor neuron disease: a clinical and preclinical systematic review. J Cell Physiol 235(6):5030–5040
Mortazavi H, Nikfar B, Esmaeili S-A, Rafieenia F, Saburi E, Chaichian S et al (2020) Potential cytotoxic and anti-metastatic effects of berberine on gynaecological cancers with drug-associated resistance. Eur J Med Chem 187:111951
Asadi G, Varmaziar FR, Karimi M, Rajabinejad M, Ranjbar S, Karaji AG et al (2021) Determination of the transcriptional level of long non-coding RNA NEAT-1, downstream target microRNAs, and genes targeted by microRNAs in diabetic neuropathy patients. Immunol Lett 232:20–26
Khosravi S, Dezfouli SMM (2020) Prevention and treatment approaches in children with the coronavirus. System Rev Pharm 11(9):913–919
Kimiaee P, Ashrafi-vand S, Mansournia MA, Bakhtiyari M, Mirzamoradi M, Bakhtiyari Z (2014) Predictive values of different forms of human chorionic gonadotropin in postmolar gestational trophoblastic neoplasia. Int J Gynecol Cancer 24(9):1715–1722
Bakhtiyari M, Mirzamoradi M, Kimyaiee P, Aghaie A, Mansournia MA, Ashrafi-Vand S et al (2015) Postmolar gestational trophoblastic neoplasia: beyond the traditional risk factors. Fertil Steril 104(3):649–654
Sun L, Liu N, Liu S-S, Xia W-Y, Liu M-Y, Li L-F et al (2015) Beclin-1-independent autophagy mediates programmed cancer cell death through interplays with endoplasmic reticulum and/or mitochondria in colbat chloride-induced hypoxia. Am J Cancer Res 5(9):2626
Liu Y, Levine B (2015) Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 22(3):367–376
Ndoye A, Weeraratna AT (2016) Autophagy-an emerging target for melanoma therapy. F1000Res 5:1888
Birgisdottir ÅB, Mouilleron S, Bhujabal Z, Wirth M, Sjøttem E, Evjen G et al (2019) Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs. Autophagy 15(8):1333–1355
Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294(5548):1942–1945
Zarzynska JM (2014) The importance of autophagy regulation in breast cancer development and treatment. Biomed Res Int. https://doi.org/10.1155/2014/710345
Fumarola C, Bonelli MA, Petronini PG, Alfieri RR (2014) Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol 90(3):197–207
Lane JD, Korolchuk VI, Murray JT, Zachari M, Ganley IG (2017) The mammalian ULK1 complex and autophagy initiation. Essays Biochem 61(6):585–596
Han D, Li S-J, Zhu Y-T, Liu L, Li M-X (2013) LKB1/AMPK/mTOR signaling pathway in non-small-cell lung cancer. Asian Pac J Cancer Prev 14(7):4033–4039
Magryś A, Bogut A, Kiełbus M, Olender A (2018) The role of the PI3K/mTOR signaling pathway in staphylococcus epidermidis small colony variants intracellular survival. Immunol Invest 47(3):251–263
Dong L-x, Sun L-l, Zhang X, Pan L, Lian L-j, Chen Z et al (2013) Negative regulation of mTOR activity by LKB1-AMPK signaling in non-small cell lung cancer cells. Acta Pharmacol Sin 34(2):314–318
Wu T, Wang M-C, Jing L, Liu Z-Y, Guo H, Liu Y et al (2015) Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway. Drug Design Develop Ther 9:6421
Li C, Dong Y, Wang L, Xu G, Yang Q, Tang X et al (2019) Ginsenoside metabolite compound K induces apoptosis and autophagy in non-small cell lung cancer cells via AMPK–mTOR and JNK pathways. Biochem Cell Biol 97(4):406–414
Wang L, Wang R (2015) Effect of rapamycin (RAPA) on the growth of lung cancer and its mechanism in mice with A549. Int J Clin Exp Pathol 8(8):9208
Abadi AH, Mahdavi M, Khaledi A, Esmaeili S-A, Esmaeili D, Sahebkar A (2018) Study of serum bactericidal and splenic activity of total-OMP-CagA combination from Brucella abortus and Helicobacter pylori in BALB/c mouse model. Microb Pathog 121:100–105
Kim KW, Moretti L, Mitchell LR, Jung DK, Lu B (2009) Combined Bcl-2/Mammalian target of rapamycin inhibition leads to enhanced radiosensitization via induction of apoptosis and autophagy in non-small cell lung tumor xenograft model. Clin Cancer Res 15(19):6096–6105
Xia Y, Liu Y-L, Xie Y, Zhu W, Guerra F, Shen S et al (2014) A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Sci Transl Med 6(263):263ra161-263ra161
Fung C, Chen X, Grandis JR, Duvvuri U (2012) EGFR tyrosine kinase inhibition induces autophagy in cancer cells. Cancer Biol Ther 13(14):1417–1424
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501
Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4:64
Vanhaesebroeck B, Alessi DR (2000) The PI3K–PDK1 connection: more than just a road to PKB. Biochem J 346(3):561–576
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101
Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE et al (2010) AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Can Res 70(1):288–298
Sini P, James D, Chresta C, Guichard S (2010) Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy 6(4):553–554
Faber AC, Li D, Song Y, Liang M-C, Yeap BY, Bronson RT et al (2009) Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci 106(46):19503–19508
Jin H-O, Lee Y-H, Park J-A, Kim J-H, Hong S-E, Kim H-A et al (2014) Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition. Biochem Biophys Res Commun 444(4):502–508
Xu C-X, Zhao L, Yue P, Fang G, Tao H, Owonikoko TK et al (2011) Augmentation of NVP-BEZ235’s anticancer activity against human lung cancer cells by blockage of autophagy. Cancer Biol Ther 12(6):549–555
Liang K-H, Tso H-C, Hung S-H, Kuan I-I, Lai J-K, Ke F-Y et al (2018) Extracellular domain of EpCAM enhances tumor progression through EGFR signaling in colon cancer cells. Cancer Lett 433:165–175
Huang Q, Li S, Zhang L, Qiao X, Zhang Y, Zhao X et al (2019) CAPE-PnO2 inhibited the growth and metastasis of triple-negative breast cancer via the EGFR/STAT3/AkT/E-cadherin signaling pathway. Front Oncol 9:461
Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A et al (2019) Publisher correction: protective autophagy elicited by RAF→ MEK→ ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med 25(5):861
Nakamura S, Oba M, Suzuki M, Takahashi A, Yamamuro T, Fujiwara M et al (2019) Suppression of autophagic activity by Rubicon is a signature of aging. Nat Commun 10(1):1–11
Bartolomeo R, Cinque L, De Leonibus C, Forrester A, Salzano AC, Monfregola J et al (2017) mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. J Clin Investig 127(10):3717–3729
Remon J, Planchard D (2015) AZD9291 in EGFR-mutant advanced non-small-cell lung cancer patients. Future Oncol 11(22):3069–3081
Han W, Pan H, Chen Y, Sun J, Wang Y, Li J et al (2011) EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS ONE 6(6):e18691
Srivastava RM, Lee SC, Andrade Filho PA, Lord CA, Jie H-B, Davidson HC et al (2013) Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen–specific T-cell immunity in head and neck cancer patients. Clin Cancer Res 19(7):1858–1872
Kol A, van Scheltinga AT, Pool M, Gerdes C, de Vries E, de Jong S (2017) ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells. Oncotarget 8(28):45432
Nagano T, Tachihara M, Nishimura Y (2019) Dacomitinib, a second-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to treat non-small cell lung cancer. Drugs Today (Barcelona, Spain: 1998) 55(4):231–236
Wang Y, Ding Q, Yen C-J, Xia W, Izzo JG, Lang J-Y et al (2012) The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell 21(3):374–387
Ke Z, Caiping S, Qing Z, Xiaojing W (2015) Sonic hedgehog–Gli1 signals promote epithelial–mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway. Med Oncol 32(1):368
Radmanesh F, Mahmoudi M, Yazdanpanah E, Keyvani V, Kia N, Nikpoor AR et al (2020) The immunomodulatory effects of mesenchymal stromal cell-based therapy in human and animal models of systemic lupus erythematosus. IUBMB Life 72(11):2366–2381
Dennler S, André J, Alexaki I, Li A, Magnaldo T, Ten Dijke P et al (2007) Induction of sonic hedgehog mediators by transforming growth factor-β: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Can Res 67(14):6981–6986
Rajurkar M, De Jesus-Monge WE, Driscoll DR, Appleman VA, Huang H, Cotton JL et al (2012) The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proc Natl Acad Sci 109(17):E1038–E1047
Huang L, Walter V, Hayes DN, Onaitis M (2014) Hedgehog–GLI signaling inhibition suppresses tumor growth in squamous lung cancer. Clin Cancer Res 20(6):1566–1575
Pietanza MC, Litvak AM, Varghese AM, Krug LM, Fleisher M, Teitcher JB et al (2016) A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer. Lung Cancer 99:23–30
Abe Y, Tanaka N (2016) The hedgehog signaling networks in lung cancer: the mechanisms and roles in tumor progression and implications for cancer therapy. Biomed Res Int 2016:1–11
Fan J, Ju D, Li Y, Wang S, Wang Z (2015) A novel approach to overcome non-small-cell lung cancer: co-inhibition of autophagy and Hedgehog pathway. Annal Oncol 26:vii106
Fan J, Zhang X, Wang S, Chen W, Li Y, Zeng X et al (2019) Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production. Cell Death Dis 10(9):1–13
Rajabinejad M, Salari F, Gorgin Karaji A, Rezaiemanesh A (2019) The role of myeloid-derived suppressor cells in the pathogenesis of rheumatoid arthritis; anti-or pro-inflammatory cells? Artif Cells, Nanomed Biotechnol 47(1):4149–4158
Kaiser J, Couzin-Frankel J (2018) Cancer immunotherapy sweeps nobel for medicine. Science 362:13
Somasundaram A, Socinski MA, Villaruz LC (2016) Immune checkpoint blockade in lung cancer. Discov Med 22(119):7–17
Rajabinejad M, Asadi G, Ranjbar S, Hezarkhani LA, Salari F, Karaji AG et al (2020) Semaphorin 4A, 4C, and 4D: function comparison in the autoimmunity, allergy, and cancer. Gene 746:144637
Fang L, Wu H-M, Ding P-S, Liu R-Y (2014) TLR2 mediates phagocytosis and autophagy through JNK signaling pathway in Staphylococcus aureus-stimulated RAW264 7 cells. Cell Signal 26(4):806–814
Keshavarz A, Pourbagheri-Sigaroodi A, Zafari P, Bagheri N, Ghaffari SH, Bashash D (2021) Toll-like receptors (TLRs) in cancer; with an extensive focus on TLR agonists and antagonists. IUBMB Life 73(1):10–25
Yazdanpanah E, Mahmoudi M, Sahebari M, Rezaieyazdi Z, Esmaeili SA, Tabasi N et al (2017) Vitamin D3 alters the expression of toll-like receptors in peripheral blood mononuclear cells of patients with systemic lupus erythematosus. J Cell Biochem 118(12):4831–4835
Pan H, Chen L, Xu Y, Han W, Lou F, Fei W et al (2016) Autophagy-associated immune responses and cancer immunotherapy. Oncotarget 7(16):21235
Oshima Y, Tanimoto T, Yuji K, Tojo A (2018) EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol 4(8):1112–1115
Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C et al (2013) Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res 19(16):4532–4540
Planchard D, Yu HA, Yang JC-H, Lee KH, Garrido Lopez P, Park K et al (2018) Efficacy and safety results of ramucirumab in combination with osimertinib in advanced T790M-positive EGFR-mutant NSCLC. Am Soc Clin Oncol 36(15):9053
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F et al (2018) Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 378(22):2078–2092
Kruse J-P, Gu W (2009) Modes of p53 regulation. Cell 137(4):609–622
Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134(3):451–460
Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8(4):275–283
Wu D, Ding Y, Wang S, Zhang Q, Liu L (2008) Increased expression of high mobility group box 1 (HMGB1) is associated with progression and poor prognosis in human nasopharyngeal carcinoma. J Pathol 216(2):167–175
Zheng H, Chen J-N, Yu X, Jiang P, Yuan L, Shen H-S et al (2016) HMGB1 enhances drug resistance and promotes in vivo tumor growth of lung cancer cells. DNA Cell Biol 35(10):622–627
Funding
2018 Xiamen medical and health guidance project funding (3502Z20199113). Clinical study on the efficacy of immunotherapy in advanced non-small-cell lung cancer (biomarker and dynamic monitoring).
Author information
Authors and Affiliations
Contributions
G. W., C. H., and M. G. contributed to the idea design and literature search. X. F. and D. H. wrote parts of the manuscript. J. Z. contributed to designing the figures. C. H. contributed in language editing and revision.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
It is not applicable.
Informed consent
It is not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wang, J., Gong, M., Fan, X. et al. Autophagy-related signaling pathways in non-small cell lung cancer. Mol Cell Biochem 477, 385–393 (2022). https://doi.org/10.1007/s11010-021-04280-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-021-04280-5