The interplay between the PI3K/AKT pathway and circadian clock in physiologic and cancer-related pathologic conditions
Received date: 01 Sep 2023
Revised date: 15 Dec 2023
Accepted date: 25 Jan 2024
Copyright
The circadian clock is responsible for the regulation of different cellular processes, and its disturbance has been linked to the development of different diseases, such as cancer. The main molecular mechanism for this issue has been linked to the crosstalk between core clock regulators and intracellular pathways responsible for cell survival. The PI3K/AKT signalling pathway is one of the most known intracellular pathways in the case of cancer initiation and progression. This pathway regulates different aspects of cell survival including proliferation, apoptosis, metabolism, and response to environmental stimuli. Accumulating evidence indicates that there is a link between the PI3K/AKT pathway activity and circadian rhythm in physiologic and cancer-related pathogenesis. Different classes of PI3Ks and AKT isoforms are involved in regulating circadian clock components in a transcriptional and functional manner. Reversely, core clock components induce a rhythmic fashion in PI3K and AKT activity in physiologic and pathogenic conditions. The aim of this review is to re-examine the interplay between this pathway and circadian clock components in normal condition and cancer pathogenesis, which provides a better understanding of how circadian rhythms may be involved in cancer progression.
Mohammad Rafi Khezri , Hsiang-Yin Hsueh , Somayeh Mohammadipanah , Javad Khalili Fard , Morteza Ghasemnejad-Berenji . The interplay between the PI3K/AKT pathway and circadian clock in physiologic and cancer-related pathologic conditions[J]. Cell Proliferation, 2024 , 57(7) : e13608 . DOI: 10.1111/cpr.13608
1 |
Koronowski KB, Sassone-Corsi P. Communicating clocks shape circadian homeostasis. Science. 2021;371(6530):eabd0951.
|
2 |
Pariollaud M, Lamia KA. Cancer in the fourth dimension: what is the impact of circadian disruption?Cancer Discov. 2020;10(10):1455-1464.
|
3 |
Lee Y, Lahens NF, Zhang S, Bedont J, Field JM, Sehgal A. G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLoS Biol. 2019;17(4):e3000228.
|
4 |
Papagiannakopoulos T, Bauer MR, Davidson SM, et al. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 2016;24(2):324-331.
|
5 |
He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6(1):425.
|
6 |
Khezri MR, Jafari R, Yousefi K, Zolbanin NM. The PI3K/AKT signaling pathway in cancer: molecular mechanisms and possible therapeutic interventions. Exp Mol Pathol. 2022;127:104787.
|
7 |
Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B. Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc Natl Acad Sci. 2007;104(19):7809-7814.
|
8 |
Gulluni F, de Santis MC, Margaria JP, Martini M, Hirsch E. Class II PI3K functions in cell biology and disease. Trends Cell Biol. 2019;29(4):339-359.
|
9 |
Backer JM. The intricate regulation and complex functions of the class III phosphoinositide 3-kinase Vps34. Biochem J. 2016;473(15):2251-2271.
|
10 |
Ktistakis NT, Tooze SA. Digesting the expanding mechanisms of autophagy. Trends Cell Biol. 2016;26(8):624-635.
|
11 |
Martini M, de Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46(6):372-383.
|
12 |
Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381-405.
|
13 |
Dummler B, Hemmings B. Physiological Roles of PKB/Akt Isoforms in Development and Disease. Portland Press Ltd.; 2007.
|
14 |
Toker A, Marmiroli S. Signaling specificity in the Akt pathway in biology and disease. Adv Biol Regul. 2014;55:28-38.
|
15 |
Liu S-L, Wang ZG, Hu Y, et al. Quantitative lipid imaging reveals a new signaling function of phosphatidylinositol-3, 4-bisphophate: isoform-and site-specific activation of Akt. Mol Cell. 2018;71(6):1092-1104.e5.
|
16 |
Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7-24.
|
17 |
Yap TA, Bjerke L, Clarke PA, Workman P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr Opin Pharmacol. 2015;23:98-107.
|
18 |
Lauring J, Cosgrove DP, Fontana S, et al. Knock in of the AKT1 E17K mutation in human breast epithelial cells does not recapitulate oncogenic PIK3CA mutations. Oncogene. 2010;29(16):2337-2345.
|
19 |
Liu J-F, Zhou XK, Chen JH, et al. Up-regulation of PIK3CA promotes metastasis in gastric carcinoma. World J Gastroenterol. 2010;16(39):4986-4991.
|
20 |
Shi J, Yao D, Liu W, et al. Highly frequent PIK3CA amplification is associated with poor prognosis in gastric cancer. BMC Cancer. 2012;12:1-11.
|
21 |
Akagi I, Miyashita M, Makino H, et al. Overexpression of PIK3CA is associated with lymph node metastasis in esophageal squamous cell carcinoma. Int J Oncol. 2009;34(3):767-775.
|
22 |
Vasan N, Razavi P, Johnson JL, et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science. 2019;366(6466):714-723.
|
23 |
Huang C-H, Mandelker D, Schmidt-Kittler O, et al. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science. 2007;318(5857):1744-1748.
|
24 |
Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci. 1987;84(14):5034-5037.
|
25 |
Liu L-Z, Zhou XD, Qian G, Shi X, Fang J, Jiang BH. AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer Res. 2007;67(13):6325-6332.
|
26 |
Cheng JQ, Godwin AK, Bellacosa A, et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci. 1992;89(19):9267-9271.
|
27 |
Nakayama K, Nakayama N, Kurman RJ, et al. Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther. 2006;5(7):779-785.
|
28 |
Soung YH, Lee JW, Nam SW, Lee JY, Yoo NJ, Lee SH. Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas. Oncology. 2006;70(4):285-289.
|
29 |
Bleeker F, Felicioni L, Buttitta F, et al. AKT1E17K in human solid tumours. Oncogene. 2008;27(42):5648-5650.
|
30 |
Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448(7152):439-444.
|
31 |
Davies M, Stemke-Hale K, Tellez C, et al. A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer. 2008;99(8):1265-1268.
|
32 |
Alcantara D, Timms AE, Gripp K, et al. Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. Brain. 2017;140(10):2610-2622.
|
33 |
Vanhaesebroeck B, Waterfield M. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999;253(1):239-254.
|
34 |
Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, immunity, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17(1):615-675.
|
35 |
Liu R, Chen Y, Liu G, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020;11(9):797.
|
36 |
Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13(22):2905-2927.
|
37 |
Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999;253(1):210-229.
|
38 |
Guertin DA, Stevens DM, Thoreen CC, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev Cell. 2006;11(6):859-871.
|
39 |
Liao Y, Hung M-C. Physiological regulation of Akt activity and stability. Am J Transl Res. 2010;2(1):19-42.
|
40 |
West KA, Castillo SS, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002;5(6):234-248.
|
41 |
Halberg F. Physiologic 24-Hour Periodicity; General and Procedural Considerations with Reference to the Adrenal Cycle. Int Z Vitaminforsch Beih. 1959;10:225.
|
42 |
Chen S-K, Badea T, Hattar S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature. 2011;476(7358):92-95.
|
43 |
Fagiani F, di Marino D, Romagnoli A, et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther. 2022;7(1):41.
|
44 |
Mure LS, Le HD, Benegiamo G, et al. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science. 2018;359(6381):eaao0318.
|
45 |
Ueyama T, Krout KE, Nguyen XV, et al. Suprachiasmatic nucleus: a central autonomic clock. Nat Neurosci. 1999;2(12):1051-1053.
|
46 |
Vujovic N, Davidson AJ, Menaker M. Sympathetic input modulates, but does not determine, phase of peripheral circadian oscillators. Am J Phys Regul Integr Comp Phys. 2008;295(1):R355-R360.
|
47 |
Buijs RM, Wortel J, van Heerikhuize JJ, et al. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci. 1999;11(5):1535-1544.
|
48 |
Kaneko M, Kaneko K, Shinsako J, Dallman MF. Adrenal sensitivity to adrenocorticotropin varies diurnally. Endocrinology. 1981;109(1):70-75.
|
49 |
Mahoney CE, Brewer D, Costello MK, Brewer JMK, Bittman EL. Lateralization of the central circadian pacemaker output: a test of neural control of peripheral oscillator phase. Am J Phys Regul Integr Comp Phys. 2010;299(3):R751-R761.
|
50 |
Ikeda M, Sugiyama T, Wallace CS, et al. Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleus neurons. Neuron. 2003;38(2):253-263.
|
51 |
Lundkvist GB, Kwak Y, Davis EK, Tei H, Block GD. A calcium flux is required for circadian rhythm generation in mammalian pacemaker neurons. J Neurosci. 2005;25(33):7682-7686.
|
52 |
O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science. 2008;320(5878):949-953.
|
53 |
Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P. Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc Natl Acad Sci. 2002;99(11):7728-7733.
|
54 |
Brum MCB, Dantas Filho FF, Schnorr CC, Bertoletti OA, Bottega GB, da Costa Rodrigues T. Night shift work, short sleep and obesity. Diabetol Metab Syndr. 2020;12:1-9.
|
55 |
Sulli G, Lam MTY, Panda S. Interplay between circadian clock and cancer: new frontiers for cancer treatment. Trends Cancer. 2019;5(8):475-494.
|
56 |
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
|
57 |
Zhang Y, Devocelle A, Souza L, et al. BMAL1 knockdown triggers different colon carcinoma cell fates by altering the delicate equilibrium between AKT/mTOR and P53/P21 pathways. Aging (Albany NY). 2020;12(9):8067-8083.
|
58 |
Tang Q, Cheng B, Xie M, et al. Circadian clock gene Bmal1 inhibits tumorigenesis and increases paclitaxel sensitivity in tongue squamous cell carcinoma. Cancer Res. 2017;77(2):532-544.
|
59 |
Jiang W, Zhao S, Jiang X, et al. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett. 2016;371(2):314-325.
|
60 |
Korkmaz T, Aygenli F, Emisoglu H, et al. Opposite carcinogenic effects of circadian clock gene BMAL1. Sci Rep. 2018;8(1):16023.
|
61 |
Fekry B, Ribas-Latre A, Baumgartner C, et al. Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma. Nat Commun. 2018;9(1):4349.
|
62 |
Peng H, Zhang J, Zhang PP, et al. ARNTL hypermethylation promotes tumorigenesis and inhibits cisplatin sensitivity by activating CDK5 transcription in nasopharyngeal carcinoma. J Exp Clin Cancer Res. 2019;38(1):1-14.
|
63 |
Gwon DH, Lee WY, Shin N, et al. BMAL1 suppresses proliferation, migration, and invasion of U87MG cells by downregulating cyclin B1, phospho-AKT, and metalloproteinase-9. Int J Mol Sci. 2020;21(7):2352.
|
64 |
Sakamoto W, Takenoshita S. Overexpression of both clock and Bmal1 inhibits entry to S phase in human colon cancer cells. Fukushima J Med Sci. 2015;61(2):111-124.
|
65 |
Louw A, Badiei A, Creaney J, Chai MS, Lee YCG. Advances in pathological diagnosis of mesothelioma: what pulmonologists should know. Curr Opin Pulm Med. 2019;25(4):354-361.
|
66 |
Puram RV, Kowalczyk MS, de Boer CG, et al. Core circadian clock genes regulate leukemia stem cells in AML. Cell. 2016;165(2):303-316.
|
67 |
Wang J, Li S, Li X, et al. Circadian protein BMAL1 promotes breast cancer cell invasion and metastasis by up-regulating matrix metalloproteinase9 expression. Cancer Cell Int. 2019;19:1-12.
|
68 |
Lee Y. Roles of circadian clocks in cancer pathogenesis and treatment. Exp Mol Med. 2021;53(10):1529-1538.
|
69 |
Chen Y, Zhu D, Yuan J, et al. CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway. Can J Physiol Pharmacol. 2016;94(9):1023-1032.
|
70 |
Dangelmaier C, Manne BK, Liverani E, Jin J, Bray P, Kunapuli SP. PDK1 selectively phosphorylates Thr(308) on Akt and contributes to human platelet functional responses. Thromb Haemost. 2014;111(3):508-517.
|
71 |
Matsumura T, Ohta Y, Taguchi A, et al. Liver-specific dysregulation of clock-controlled output signal impairs energy metabolism in liver and muscle. Biochem Biophys Res Commun. 2021;534:415-421.
|
72 |
Aviram R, Dandavate V, Manella G, Golik M, Asher G. Ultradian rhythms of AKT phosphorylation and gene expression emerge in the absence of the circadian clock components Per1 and Per2. PLoS Biol. 2021;19(12):e3001492.
|
73 |
Nakao T, Kohsaka A, Otsuka T, et al. Impact of heart-specific disruption of the circadian clock on systemic glucose metabolism in mice. Chronobiol Int. 2018;35(4):499-510.
|
74 |
McGinnis GR, Tang Y, Brewer RA, et al. Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart. J Mol Cell Cardiol. 2017;110:80-95.
|
75 |
Zhang D, Tong X, Arthurs B, et al. Liver clock protein BMAL1 promotes de novo lipogenesis through insulin-mTORC2-AKT signaling. J Biol Chem. 2014;289(37):25925-25935.
|
76 |
McKenna M, Balasuriya N, Zhong S, Li SSC, O'Donoghue P. Phospho-form specific substrates of protein kinase B (AKT1). Front Bioeng Biotechnol. 2021;8:619252.
|
77 |
Wang Y, Chen M, Xu J, et al. Core clock gene Bmal1 deprivation impairs steroidogenesis in mice luteinized follicle cells. Reproduction. 2020;160(6):955-967.
|
78 |
Wang W, Yin L, Bai L, et al. Bmal1 interference impairs hormone synthesis and promotes apoptosis in porcine granulosa cells. Theriogenology. 2017;99:63-68.
|
79 |
Alkhoury C, Henneman NF, Petrenko V, et al. Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis. Nat Cell Biol. 2023;25(7):975-988.
|
80 |
Morishita Y, Miura D, Kida S. PI3K regulates BMAL1/CLOCK-mediated circadian transcription from the Dbp promoter. Biosci Biotechnol Biochem. 2016;80(6):1131-1140.
|
81 |
Luciano AK, Santana JM, Velazquez H, Sessa WC. Akt1 controls the timing and amplitude of vascular circadian gene expression. J Biol Rhythms. 2017;32(3):212-221.
|
82 |
Yoshitane H, Imamura K, Okubo T, et al. mTOR-AKT signaling in cellular clock resetting triggered by osmotic stress. Antioxid Redox Signal. 2022;37(10–12):631-646.
|
83 |
Luciano AK, Zhou W, Santana JM, Kyriakides C, Velazquez H, Sessa WC. CLOCK phosphorylation by AKT regulates its nuclear accumulation and circadian gene expression in peripheral tissues. J Biol Chem. 2018;293(23):9126-9136.
|
84 |
Dang F, Sun X, Ma X, et al. Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock. Nat Commun. 2016;7(1):12696.
|
85 |
Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone-Corsi P. Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PloS One. 2010;5(1):e8561.
|
86 |
Chen K, Li HX, Li YH, Yang ZY, Luo J, Zhou Z. ARNTL inhibits the malignant behaviors of oral cancer by regulating autophagy in an AKT/mTOR pathway-dependent manner. Cancer Sci. 2023;114:3914-3923.
|
87 |
Wang Y, Qian R, Sun N, Lu C, Chen Z, Hua L. Circadian gene hClock enhances proliferation and inhibits apoptosis of human colorectal carcinoma cells in vitro and in vivo. Mol Med Rep. 2015;11(6):4204-4210.
|
88 |
Qin T, Lu XT, Li YG, et al. Effect of period 2 on the proliferation, apoptosis and migration of osteosarcoma cells, and the corresponding mechanisms. Oncol Lett. 2018;16(2):2668-2674.
|
89 |
Xiong H, Yang Y, Yang K, Zhao D, Tang H, Ran X. Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer. Int J Oncol. 2018;52(1):279-287.
|
90 |
Zhou L, Yu Y, Sun S, Zhang T, Wang M. Cry 1 regulates the clock gene network and promotes proliferation and migration via the Akt/P53/P21 pathway in human osteosarcoma cells. J Cancer. 2018;9(14):2480-2491.
|
91 |
Yu M, Li W, Wang Q, Wang Y, Lu F. Circadian regulator NR1D2 regulates glioblastoma cell proliferation and motility. Oncogene. 2018;37(35):4838-4853.
|
92 |
Guo L, Cen H, Weng J, et al. PER2 integrates circadian disruption and pituitary tumorigenesis. Theranostics. 2023;13(8):2657-2672.
|
93 |
Schwartz PB, Nukaya M, Berres ME, et al. The circadian clock is disrupted in pancreatic cancer. PLoS Genet. 2023;19(6):e1010770.
|
94 |
Relles D, Sendecki J, Chipitsyna G, Hyslop T, Yeo CJ, Arafat HA. Circadian gene expression and clinicopathologic correlates in pancreatic cancer. J Gastrointest Surg. 2013;17(3):443-450.
|
95 |
Li W, Liu L, Liu D, et al. Decreased circadian component Bmal1 predicts tumor progression and poor prognosis in human pancreatic ductal adenocarcinoma. Biochem Biophys Res Commun. 2016;472(1):156-162.
|
96 |
Hermyt E, Zmarzly N, Kruszniewska-Rajs C, et al. Expression pattern of circadian rhythm-related genes and its potential relationship with miRNAs activity in endometrial cancer. Ginekol pol. 2023;94(1):33-40.
|
97 |
Lesicka M, Nedoszytko B, Reszka E. Disruptions of circadian genes in cutaneous melanoma-an in silico analysis of transcriptome databases. Int J Mol Sci. 2023;24(12):10140.
|
98 |
He A, Huang Z, Zhang R, et al. Circadian clock genes are correlated with prognosis and immune cell infiltration in colon adenocarcinoma. Comput Math Methods Med. 2022;2022:1709918.
|
99 |
He Y, Chen Y, Dai X, Huang S. Dysregulation of circadian clock genes associated with tumor immunity and prognosis in patients with colon cancer. Comput Math Methods Med. 2022;2022:4957996.
|
100 |
Orhan T, Nielsen PB, Hviid TVF, Rosen AW, Gögenür I. Expression of circadian clock genes in human colorectal cancer tissues using droplet digital PCR. Cancer Investig. 2019;37(2):90-98.
|
101 |
Yu H, Meng X, Wu J, et al. Cryptochrome 1 overexpression correlates with tumor progression and poor prognosis in patients with colorectal cancer. PloS One. 2013;8(4):e61679.
|
102 |
Krugluger W, Brandstaetter A, Kállay Ë, et al. Regulation of genes of the circadian clock in human colon cancer: reduced period-1 and dihydropyrimidine dehydrogenase transcription correlates in high-grade tumors. Cancer Res. 2007;67(16):7917-7922.
|
103 |
Huisman SA, Ahmadi AR, IJzermans JNM, Verhoef C, van der Horst GTJ, de Bruin RWF. Disruption of clock gene expression in human colorectal liver metastases. Tumour Biol. 2016;37(10):13973-13981.
|
104 |
Hu ML, Yeh KT, Lin PM, et al. Deregulated expression of circadian clock genes in gastric cancer. BMC Gastroenterol. 2014;14:67.
|
105 |
Hsu CM, Lin SF, Lu CT, Lin PM, Yang MY. Altered expression of circadian clock genes in head and neck squamous cell carcinoma. Tumour Biol. 2012;33(1):149-155.
|
106 |
van der Watt PJ, Roden LC, Davis KT, Parker MI, Leaner VD. Circadian oscillations persist in cervical and esophageal cancer cells displaying decreased expression of tumor-suppressing circadian clock genes. Mol Cancer Res. 2020;18(9):1340-1353.
|
107 |
de Assis LVM, Kinker GS, Moraes MN, Markus RP, Fernandes PA, Castrucci AML. Expression of the circadian clock gene BMAL1 positively correlates with antitumor immunity and patient survival in metastatic melanoma. Front Oncol. 2018;8:185.
|
108 |
Broadberry E, McConnell J, Williams J, et al. Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours. Breast Cancer Res. 2018;20(1):125.
|
109 |
Moreno-Smith M, Milazzo G, Tao L, et al. Restoration of the molecular clock is tumor suppressive in neuroblastoma. Nat Commun. 2021;12(1):4006.
|
110 |
Anea CB, Zhang M, Stepp DW, et al. Vascular disease in mice with a dysfunctional circadian clock. Circulation. 2009;119(11):1510-1517.
|
111 |
Lin RJ, Dai XF. Sleep deprivation affects sex hormones secretion by regulating the expression of the circadian clock gene in the hypothalamus and pituitary via the PI3K/Akt signaling pathway in pregnant rats. Sheng Li Xue Bao. 2022;74(4):534-540.
|
112 |
Ding H, Zhao J, Liu H, Wang J, Lu W. BMAL1 knockdown promoted apoptosis and reduced testosterone secretion in TM3 Leydig cell line. Gene. 2020;747:144672.
|
113 |
Carvas JM, Vukolic A, Yepuri G, et al. Period2 gene mutant mice show compromised insulin-mediated endothelial nitric oxide release and altered glucose homeostasis. Front Physiol. 2012;3:337.
|
114 |
Jiang Y, Wang S, Lin W, Gu J, Li G, Shao Y. BMAL1 promotes valvular interstitial cells' osteogenic differentiation through NF-κ B/AKT/MAPK pathway. J Cardiovasc Dev Dis. 2023;10(3):110.
|
115 |
Nobis CC, Dubeau Laramée G, Kervezee L, Maurice de Sousa D, Labrecque N, Cermakian N. The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways. Proc Natl Acad Sci USA. 2019;116(40):20077-20086.
|
116 |
Zhou L, He J, Sun S, Yu Y, Zhang T, Wang M. Cryptochrome 1 regulates osteoblast differentiation via the AKT kinase and extracellular signal-regulated kinase signaling pathways. Cell Reprogram. 2019;21(3):141-151.
|
117 |
Jung CH, Kim EM, Park JK, et al. Bmal1 suppresses cancer cell invasion by blocking the phosphoinositide 3-kinase-Akt-MMP-2 signaling pathway. Oncol Rep. 2013;29(6):2109-2113.
|
118 |
Lu M, Huang L, Tang Y, et al. ARNTL2 knockdown suppressed the invasion and migration of colon carcinoma: decreased SMOC2-EMT expression through inactivation of PI3K/AKT pathway. Am J Transl Res. 2020;12(4):1293-1308.
|
119 |
Yang Y, Bai Y, Wang X, et al. Clock gene NR1D1 might be a novel target for the treatment of bladder cancer. Urol Oncol. 2023;41(7):327.e9-327.e18.
|
120 |
Zhou J, Tang ZY, Sun XL. RNF38 inhibits osteosarcoma cell proliferation by binding to CRY1. Biochem Cell Biol. 2021;99(5):629-635.
|
121 |
Chen B, Tan Y, Liang Y, et al. Per2 participates in AKT-mediated drug resistance in A549/DDP lung adenocarcinoma cells. Oncol Lett. 2017;13(1):423-428.
|
122 |
Wang Z, Li F, Wei M, Zhang S, Wang T. Circadian clock protein PERIOD2 suppresses the PI3K/Akt pathway and promotes cisplatin sensitivity in ovarian cancer. Cancer Manag Res. 2020;12:11897-11908.
|
123 |
Wang Z, Wang H, Guo H, et al. The circadian rhythm and core gene Period2 regulate the chemotherapy effect and multidrug resistance of ovarian cancer through the PI3K signaling pathway. Biosci Rep. 2020;40(11):BSR20202683.
|
/
〈 | 〉 |