Phosphatidylinositol-3-kinase/Protein Kinase B Signaling Pathway: A Pivotal Factor for Stimulating Multidrug Resistance in Hepatocellular Carcinoma Cells

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Chao Zhang, Mengsen Li, Mingyue Zhu

Abstract


Hepatocellular carcinoma (HCC) is a common malignant tumor. Chemotherapy is one of its principal modes of treatment, but multidrug resistance (MDR) poses an obstacle in HCC treatment. MDR is mainly mediated through drug transmembrane transporter activity, apoptosis inhibitory pathway abnormality, and changes in the intracellular enzyme. On top of that, phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway dysregulation is also one of the most common mechanisms of MDR. This signaling pathway plays critical roles in the differentiation, proliferation, and apoptosis of cancer cells, and is a new target of MDR treatment. This review article discusses the mechanisms of MDR in HCC with a strong emphasis on the significance and role of PI3K/Akt pathway in MDR, and the reversal of MDR by inhibiting PI3K/Akt pathway.


Keywords


Hepatocellular carcinoma, Multidrug resistance, PI3K/AKT pathway

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Siegel RL, Miller KD, Fuchs HE, et al., 2021, Cancer Statistics. CA Cancer J Clin, 70(1):7–33. DOI: 10.3322/ caac.21654.

Assaraf YG, Brozovic A, Goncalves AC, et al., 2019, The Multi-Factorial Nature of Clinical Multidrug Resistance in Cancer. Drug Resist Updat, 46:100645. DOI: 10.1016/j. drup.2019.100645.

Yang Q, Jiang W, Hou P, 2019, Emerging Role of PI3K/AKT in Tumor-Related Epigenetic Regulation. Semin Cancer Biol, 59:112–24. DOI: 10.1016/j.semcancer.2019.04.001.

Alzahrani AS, 2019, PI3K/Akt/mTOR Inhibitors in Cancer: At the Bench and Bedside. Semin Cancer Biol, 59:125–32. DOI: 10.1016/j.semcancer.2019.07.009.

Janku F, Yap TA, Meric-Bernstam F, 2018, Targeting the PI3K Pathway in Cancer: Are We Making Headway? Nat Rev Clin Oncol, 15(5):273–91. DOI: 10.1038/ nrclinonc.2018.28.

Jiang N, Dai Q, Su X, et al., 2020, Role of PI3K/AKT Pathway in Cancer: The Framework of Malignant Behavior. Mol Biol Rep, 47(6):4587–629. DOI: 10.1007/s11033-020- 05435-1.

Kirstein MM, Boukouris AE, Pothiraju D, et al., 2013, Activity of the mTOR Inhibitor RAD001, the Dual mTOR and PI3-Kinase Inhibitor BEZ235 and the PI3-Kinase Inhibitor BKM120 in Hepatocellular Carcinoma. Liver Int, 33(5):780–93. DOI: 10.1111/liv.12126.

Fruman DA, Chiu H, Hopkins BD, et al., 2017, The PI3K Pathway in Human Disease. Cell, 170(4):605–35. DOI: 10.1016/j.cell.2017.07.029.

Hoxhaj G, Manning BD, 2020, The PI3K-AKT Network at the Interface of Oncogenic Signalling and Cancer Metabolism. Nat Rev Cancer, 20(2):74–88. DOI: 10.1038/ s41568-019-0216-7.

Manning BD, Toker A, 2017, AKT/PKB Signaling: Navigating the Network. Cell, 169(3):381–405. DOI: 10.1016/j.cell.2017.04.001.

Osorio-Fuentealba C, Klip A, 2015, Dissecting Signalling by Individual Akt/PKB Isoforms, Three Steps at Once. Biochem J, 470(2):e13–6. DOI: 10.1042/bj20150750.

Revathidevi S, Munirajan AK, 2019, Akt in Cancer: Mediator and More. Semin Cancer Biol, 59:80–91. DOI: 10.1016/j.semcancer.2019.06.002.

Okkenhaug K, Graupera M, Vanhaesebroeck B, 2019, Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov, 6(10):1090–105. DOI: 10.1158/2159-8290. cd-16-0716.

Kale J, Kutuk O, Brito GC, et al., 2018, Phosphorylation Switches Bax from Promoting to Inhibiting Apoptosis Thereby Increasing Drug Resistance. EMBO Rep, 19(9):e45235. DOI: 10.15252/embr.201745235.

Chen H, Zhou B, Yang J, et al., 2018, Essential Oil Derived from Eupatorium Adenophorum Spreng. Mediates Anticancer Effect by Inhibiting STAT3 and AKT Activation to Induce Apoptosis in Hepatocellular Carcinoma. Front Pharmacol, 9:483. DOI: 10.3389/fphar.2018.00483.

Jin S, Borkhuu O, Bao W, et al., 2016, Signaling Pathways in Thyroid Cancer and Their Therapeutic Implications. J Clin Med Res, 8(4):284–96. DOI: 10.14740/jocmr2480w.

Nagini S, Sophia J, Mishra R, 2019, Glycogen Synthase Kinases: Moonlighting Proteins with Theranostic Potential in Cancer. Semin Cancer Biol, 56:25–36. DOI: 10.1016/j. semcancer.2017.12.010.

Ma X, Zhou F, Chen Y, et al., 2014, A Polysaccharide from Grifola frondosa Relieves Insulin Resistance of HepG2 Cell by Akt-GSK-3 Pathway. Glycoconj J, 31(5):355–63. DOI: 10.1007/s10719-014-9526-x.

Brown JS, Banerji U, 2017, Maximising the Potential of AKT Inhibitors as Anti-Cancer Treatments. Pharmacol Ther, 172:101–15. DOI: 10.1016/j.pharmthera.2016.12.001.

Lorusso PM, 2016, Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors. J Clin Oncol, 34(31):3803–15. DOI: 10.1200/jco.2014.59.0018.

Tarling EJ, de Aguiar VT, Edwards PA, 2013, Role of ABC Transporters in Lipid Transport and Human Disease. Trends Endocrinol Metab, 24(7):342–50. DOI: 10.1016/j. tem.2013.01.006.

El-Awady R, Saleh E, Hashim A, et al., 2016, The Role of Eukaryotic and Prokaryotic ABC Transporter Family in Failure of Chemotherapy. Front Pharmacol, 7:535. DOI: 10.3389/fphar.2016.00535.

Robey RW, Pluchino KM, Hall MD, et al., 2018, Revisiting the Role of ABC transporters in Multidrug-Resistant Cancer. Nat Rev Cancer, 18(7):452–64. DOI: 10.1038/s41568-018- 0005-8.

Chung FS, Santiago JS, Jesus MF, et al., 2016, Disrupting P-Glycoprotein Function in Clinical Settings: What Can We Learn from the Fundamental Aspects of This Transporter? Am J Cancer Res, 6(8):1583–98.

Meng Q, He X, Xie G, et al., 2017, MEK Inhibitor Enhances Sensitivity to Chemotherapeutic Drugs in Multidrug Resistant Hepatocellular Carcinoma Cells. Oncol Lett, 14(3):3089–95. DOI: 10.3892/ol.2017.6494.

Yahya SM, Fathy SA, El-Khayat ZA, et al., 2018, Possible Role of MicroRNA-122 in Modulating Multidrug Resistance of Hepatocellular Carcinoma. Indian J Clin Biochem, 33(1):21–30. DOI: 10.1007/s12291-017-0651-8.

Jackson SM, Manolaridis I, Kowal J, et al., 2018, Structural Basis of Small-molecule Inhibition of Human Multidrug Transporter ABCG2. Nat Struct Mol Biol, 25(4):333–40. DOI: 10.1038/s41594-018-0049-1.

Guo YY, Wu Y, Jia XW, et al., 2017, Augmenter of Liver Regeneration Potentiates Doxorubicin Anticancer Efficacy by Reducing the Expression of ABCB1 and ABCG2 in Hepatocellular Carcinoma. Lab Invest, 97(12):1400–11. DOI: 10.1038/labinvest.2017.72.

Li H, Zhou S, Li T, et al., 2012, Suppression of BCRP Expression and Restoration of Sensitivity to Chemotherapyin Multidrug-Resistant HCC Cell Line HEPG2/ADM by RNA Interference. Hepatogastroenterology, 59(119):2238–42. DOI: 10.5754/hge11781.

Allocati N, Masulli M, di Ilio C, et al., 2018, Glutathione Transferases: Substrates, Inihibitors and Pro-drugs in Cancer and Neurodegenerative Diseases. Oncogenesis, 7(1):8. DOI: 10.1038/s41389-017-0025-3.

Huang H, Chen J, Ding CM, et al., 2018, LncRNA NR2F1- AS1 Regulates Hepatocellular Carcinoma Oxaliplatin Resistance by Targeting ABCC1 Via MiR-363. J Cell Mol Med, 22(6):3238–45. DOI: 10.1111/jcmm.13605.

Kataoka J, Shiraha H, Horiguchi S, et al., 2017, Loss of Runt-Related Transcription Factor 3 Induces Resistance to 5-Fluorouracil and Cisplatin in Hepatocellular Carcinoma. Oncol Rep, 37(3):1921. DOI: 10.3892/or.2017.5419.

Roake CM, Artandi SE, 2020, Regulation of Human Telomerase in Homeostasis and Disease. Nat Rev Mol Cell Biol, 21(7):384–97. DOI: 10.1038/s41580-020-0234-z.

Lipinska N, Romaniuk A, Paszel-Jaworska A, et al., 2017, Telomerase and Drug Resistance in Cancer. Cell Mol Life Sci, 74(22):4121–32. DOI: 10.1007/s00018-017-2573-2.

Shay JW, 2016, Role of Telomeres and Telomerase in Aging and Cancer. Cancer Discov, 6(6):584–93. DOI: 10.1158/2159-8290.cd-16-0062.

Dong X, Liu A, Zer C, et al., 2009, SiRNA Inhibition of Telomerase Enhances the Anti-Cancer Effect of Doxorubicin in Breast Cancer Cells. BMC Cancer, 9:133. DOI: 10.1186/1471-2407-9-133.

Smith V, Dai F, Spitz M, et al., 2009, Telomerase Activity and Telomere Length in Human Tumor Cells with Acquired Resistance to Anticancer Agents. J Chemother, 21(5):542– 9. DOI: 10.1179/joc.2009.21.5.542.

Kuranaga N, Shinomiya N, Mochizuki H, 2001, Long-Term Cultivation of Colorectal Carcinoma Cells with Anti-Cancer Drugs Induces Drug Resistance and Telomere Elongation: An In Vitro Study. BMC Cancer, 1:10. DOI: 10.1186/1471- 2407-1-10.

Ling X, Wen L, Zhou Y, 2012, Role of Mitochondrial Translocation of Telomerase in Hepatocellular Carcinoma Cells with Multidrug Resistance. Int J Med Sci, 9(7):545– 54. DOI: 10.7150/ijms.4648.

Dong SC, Sha HH, Xu XY, et al., 2018, Glutathione S-Transferase Pi: A Potential Role in Antitumor Therapy. Drug Des Devel Ther, 12:3535–47. DOI: 10.2147/DDDT. S169833.

Lu F, Hou YQ, Song Y, et al., 2013, TFPI-2 Downregulates Multidrug Resistance Protein in 5-FU-Resistant Human Hepatocellular Carcinoma BEL-7402/5-FU Cells. Anat Rec (Hoboken), 296(1):56–63. DOI: 10.1002/ar.22611.

Sochalska M, Tuzlak S, Egle A, 2015, Lessons from Gain-and Loss-of-Function Models of Pro-Survival Bcl2 Family Proteins: Implications for Targeted Therapy. FEBS J, 282:834–49. DOI: 10.1111/febs.13188.

Shojaei F, Yazdani-Nafchi F, Banitalebi-Dehkordi M, et al., 2019, Trace of Survivin in Cancer. Eur J Cancer Prev, 28(4):365–72. DOI: 10.1097/cej.0000000000000453.

Singh R, Letai A, Sarosiek K, 2019, Regulation of Apoptosis in Health and Disease: The Balancing Act of BCL-2 Family Proteins. Nat Rev Mol Cell Biol, 20(3):175–93. DOI: 10.1038/s41580-018-0089-8.

Sawant DA, Tharakan B, Hunter FA, et al., 2014, The Role of Intrinsic Apoptotic Signaling in Hemorrhagic Shock-Induced Microvascular Endothelial Cell Barrier Dysfunction. J Cardiovasc Transl Res, 7(8):711–8. DOI: 10.1007/s12265-014-9589-x.

Li Y, Tan X, Liu X, et al., 2020, Enhanced Anticancer Effect of Doxorubicin by TPGS-Coated Liposomes with Bcl-2 siRNA-Corona for Dual Suppression of Drug Resistance. Asian J Pharm Sci, 15(5):646–60. DOI: 10.1016/j. ajps.2019.10.003.

Fang S, Qiu J, Wu Z, et al., 2017, Down-Regulation of UBC9 Increases the Sensitivity of Hepatocellular Carcinoma to Doxorubicin. Oncotarget, 8(30):49783–95. DOI: 10.18632/ oncotarget.17939.

Yang X, Yin J, Xiang Q, et al., 2017, MiR-503 Sensitizes Human Hepatocellular Carcinoma Cells to Cisplatin by Targeting Bcl-2. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 42(6):605–10. DOI: 10.11817/j.issn.1672- 7347.2017.06.001.

Mobahat M, Narendran A, Riabowol K, 2014, Survivin as a Preferential Target for Cancer Therapy. Int J Mol Sci, 15(2):2494–516. DOI: 10.3390/ijms15022494.

Rathore R, Mccallum JE, Varghese E, et al., 2017, Overcoming Chemotherapy Drug Resistance by Targeting Inhibitors of Apoptosis Proteins (IAPs). Apoptosis, 22(7):898–919. DOI: 10.1007/s10495-017-1375-1.

Ho CT, Shang HS, Chang JB, et al., 2015, Folate Deficiency- Triggered Redox Pathways Confer Drug Resistance in Hepatocellular Carcinoma. Oncotarget, 6(28):26104–18. DOI: 10.18632/oncotarget.4422.

Liu G, Yuan X, Zeng Z, et al., 2006, Analysis of Gene Expression and Chemoresistance of CD133+Cancer Stem Cells in Glioblastoma. Mol Cancer, 5:67. DOI: 10.1186/1476-4598-5-67.

Zhang Q, Lenardo MJ, Baltimore D, 2017, 30 Years of NF-kappaB: A Blossoming of Relevance to Human Pathobiology. Cell, 168(1–2):37–57. DOI: 10.1016/j. cell.2016.12.012.

Sun SC, 2017, The Non-Canonical NF-KappaB Pathway in Immunity and Inflammation. Nat Rev Immunol, 17(9): 545–58. DOI: 10.1038/nri.2017.52.

Bonavida B, 2014, RKIP-Mediated Chemo- Immunosensitization of Resistant Cancer Cells Via Disruption of the NF-κB/Snail/YY1/RKIP Resistance- Driver Loop. Crit Rev Oncog, 19(6):431–45. DOI: 10.1615/ critrevoncog.2014011929.

Yang HY, Zhao L, Yang Z, et al., 2012, Oroxylin A Reverses Multi-drug Resistance of Human Hepatoma BEL7402/5-FU Cells Via Downregulation of P-Glycoprotein Expression by Inhibiting NF-KappaB Signaling Pathway. Mol Carcinog, 51(2):185–95. DOI: 10.1002/mc.20789.

Liu T, Wei R, Zhang Y, et al., 2019, Association between NF-KappaB Expression and Drug Resistance of Liver Cancer. Oncol Lett, 17(1):1030–4. DOI: 10.3892/ol.2018.9640.

Liu R, Chen Y, Liu G, et al., 2020, PI3K/AKT Pathway as a Key Link Modulates the Multidrug Resistance of Cancers. Cell Death Dis, 11(9):797. DOI: 10.1038/s41419-020- 02998-6.

Cheng L, Luo S, Jin C, et al., 2013, FUT Family Mediates the Multidrug Resistance of Human Hepatocellular Carcinoma Via the PI3K/Akt Signaling Pathway. Cell Death Dis, 4:e923. DOI: 10.1038/cddis.2013.450.

Yang C, Hou A, Yu C, et al., 2018, Kanglaite Reverses Multidrug Resistance of HCC by Inducing Apoptosis and Cell Cycle Arrest Via PI3K/AKT Pathway. Onco Targets Ther, 11:983–96. DOI: 10.2147/ott.s153814.

Xie Y, Zhong DW, 2016, AEG-1 Is Associated with Hypoxia- Induced Hepatocellular Carcinoma Chemoresistance Via Regulating PI3K/AKT/HIF-1alpha/MDR-1 Pathway. EXCLI J, 15:745–57. DOI: 10.17179/excli2016-694.

Chebel A, Ffrench M, 2010, Transcriptional Regulation of the Human Telomerase Reverse Transcriptase: New Insights. Transcription, 1(1):27–31. DOI: 10.4161/trns.1.1.12062.

Dogan F, Biray AC, 2018, Correlation between Telomerase and MTOR Pathway in Cancer Stem Cells. Gene, 641:235– 9. DOI: 10.1016/j.gene.2017.09.072.

Tahtouh R, Azzi AS, Alaaeddine N, et al., 2015, Telomerase Inhibition Decreases Alpha-Fetoprotein Expression and Secretion by Hepatocellular Carcinoma Cell Lines: In Vitro and In Vivo Study. PLoS One, 10(3):e0119512. DOI: 10.1371/journal.pone.0119512.

Warren CF, Wong-Brown MW, Bowden NA, 2019, BCL-2 Family Isoforms in Apoptosis and Cancer. Cell Death Dis, 10(3):177. DOI: 10.1038/s41419-019-1407-6.

Tang GE, Niu YX, Li Y, et al., 2020, Paris Saponin VII Enhanced the Sensitivity of HepG2/ADR Cells to ADR Via Modulation ofPI3K/AKT/MAPK Signaling Pathway. Kaohsiung J Med Sci, 36(2):98–106. DOI: 10.1002/ kjm2.12145.

Ma J, Matkar S, He X, et al., 2018, FOXO Family in Regulating Cancer and Metabolism. Semin Cancer Biol, 50:32–41. DOI: 10.1016/j.semcancer.2018.01.018.

Jiang J, Huang Z, Chen X, et al., 2017, Trifluoperazine Activates FOXO1-Related Signals to Inhibit Tumor Growth in Hepatocellular Carcinoma. DNA Cell Biol, 36(10):813– 21. DOI: 10.1089/dna.2017.3790.

Link W, 2019, Introduction to FOXO Biology. Methods Mol Biol, 1890:1–9. DOI: 10.1007/978-1-4939-8900-3_1.

Lu M, Hartmann D, Braren R, et al., 2019, Oncogenic Akt-FOXO3 Loop Favors Tumor-Promoting Modes and Enhances Oxidative Damage-associated Hepatocellular Carcinogenesis. BMC Cancer, 9(1):887. DOI: 10.1186/ s12885-019-6110-6.

Ghoneum A, Said N, 2019, PI3K-AKT-mTOR and NFkappaB Pathways in Ovarian Cancer: Implications for Targeted Therapeutics. Cancers (Basel), 11(7):949. DOI: 10.3390/cancers11070949.

Sui H, Pan SF, Feng Y, et al., 2014, Zuo Jin Wan Reverses P-gp-Mediated Drug-Resistance by Inhibiting Activation of the PI3K/Akt/NF-KappaB Pathway. BMC Complement Altern Med, 14:279. DOI: 10.1186/1472-6882-14-279.

Wang D, Zhang N, Ye Y, et al., 2014, Role and Mechanisms of MicroRNA503 in Drug Resistance Reversal in HepG2/ ADM Human Hepatocellular Carcinoma Cells. Mol Med Rep, 10(6):3268–74. DOI: 10.3892/mmr.2014.2591.

Zhang H, Wang Q, Liu J, et al., 2018, Inhibition of the PI3K/Akt Signaling Pathway Reverses Sorafenib-Derived Chemo-Resistance in Hepatocellular Carcinoma. Oncol Lett, 15(6):9377–84. DOI: 10.3892/ol.2018.8536.

He K, Yu X, Wang X, et al., 2018, Baicalein and Ly294002 Induces Liver Cancer Cells Apoptosis Via Regulating Phosphatidyl Inositol 3-Kinase/Akt signaling Pathway. J Cancer Res Ther, 14: S519–25. DOI: 10.4103/0973- 1482.235356.

Sun B, Xu HY, Zhang G, et al., 2013, Basic Fibroblast Growth Factor Upregulates Survivin Expression in Hepatocellular Carcinoma Cells Via a Protein Kinase B-Dependent Pathway. Oncol Rep, 30(1):385–90. DOI: 10.3892/or.2013.2479.

Hanker AB, Kaklamani V, Arteaga CL, 2019, Challenges For the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors. Cancer Discov, 9(4):482–91. DOI: 10.1158/2159-8290.cd-18-1175.

Hu Y, Guo R, Wei J, et al., 2015, Effects of PI3K Inhibitor NVP-BKM120 on Overcoming Drug Resistance and Eliminating Cancer Stem Cells in Human Breast Cancer Cells. Cell Death Dis, 6:e2020. DOI: 10.1038/ cddis.2015.363.

Nitulescu GM, Margina D, Juzenas P, et al., 2016, Akt Inhibitors in Cancer Treatment: The Long Journey from Drug Discovery to Clinical Use (Review). Int J Oncol, 48(3):869–85. DOI: 10.3892/ijo.2015.3306.

Agarwal E, Chaudhuri A, Leiphrakpam PD, et al., 2014, Akt Inhibitor MK-2206 Promotes Anti-tumor Activity and Cell Death by Modulation of AIF and Ezrin in Colorectal Cancer. BMC Cancer, 14:145. DOI: 10.1186/1471-2407-14-145.

Simioni C, Martelli AM, Cani A, et al., 2013, The AKT Inhibitor MK-2206 is Cytotoxic in Hepatocarcinoma Cells Displaying Hyperphosphorylated AKT-1 and Synergizes with Conventional Chemotherapy. Oncotarget, 4(9):1496– 506. DOI: 10.18632/oncotarget.1236.

Mundi PS, Sachdev J, Mccourt C, et al., 2016, AKT in Cancer: New Molecular Insights and Advances in Drug Development. Br J Clin Pharmacol, 82(4):943–56. DOI: 10.1111/bcp.13021.

Fei HR, Chen G, Wang JM, et al., 2010, Perifosine Induces Cell Cycle Arrest and Apoptosis in Human Hepatocellular Carcinoma Cell Lines by Blockade of Akt Phosphorylation. Cytotechnology, 62(5):449–60. DOI: 10.1007/s10616-010- 9299-4.

Zhu M, Lin B, Zhou P, et al., 2015, Molecular Analysis of AFP and HSA Interactions with PTEN Protein. Biomed Res Int, 2015:256916. DOI: 10.1155/2015/256916.

Zhu M, Guo J, Xia H, et al., 2015, Alpha-Fetoprotein Activates AKT/mTOR Signaling to Promote CXCR4 Expression and Migration of Hepatoma Cells. Oncoscience, 2(1):59–70. DOI: 10.18632/oncoscience.115.

Xue J, Cao Z, Cheng Y, et al., 2020, Acetylation of Alpha-Fetoprotein Promotes Hepatocellular Carcinoma Progression. Cancer Lett, 471:12–26. DOI: 10.1016/j. canlet.2019.11.043.

Wang S, Zhu M, Wang Q, et al., 2018, Alpha-Fetoprotein Inhibits Autophagy to Promote Malignant Behaviour in Hepatocellular Carcinoma Cells by Activating PI3K/ AKT/mTOR Signalling. Cell Death Dis, 9(10):1027. DOI: 10.1038/s41419-018-1036-5.




DOI: http://dx.doi.org/10.18063/ghl.v3i1.265

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