雄激素受体与PI3K/AKT通路相互作用机制在前列腺癌中的研究进展

doi:10.3969/j.issn.1006-7795.2025.02.013

摘要/Abstract

摘要： 雄激素受体通路与磷脂酰肌醇3-激酶（phosphatidylinositide 3-kinases，PI3K）/AKT通路均在前列腺癌的疾病进展中占据着举足轻重的地位。两条通路之间存在着错综复杂的相互作用，彼此间展现出相互制约的负向调节关系。鉴于此，针对这两条通路的联合抑制策略有望成为前列腺癌治疗的重要途径。本文旨在全面综述雄激素受体与PI3K/AKT通路相互作用的分子机制，以期为相关领域的研究提供新的视角与启示。

关键词: 前列腺癌, 雄激素受体, PI3K, AKT, 信号通路

Abstract: Both the androgen receptor pathway and PI3K/AKT pathway play pivotal roles in the progression of prostate cancer. There are intricate interactions between these two pathways, showing a negative regulatory relationship of mutual restriction between them. In view of the above, a combined inhibition strategy targeting these two pathways is expected to become a significant therapeutic approach for prostate cancer. This article aims to comprehensively review the molecular mechanisms underlying the interactions between the androgen receptor and PI3K/AKT pathways, to provide new perspectives and insights for research in the fields.

Key words: prostate cancer, androgen receptor, PI3K, AKT, signaling pathway

中图分类号:

R737.25

熊天宇, 赵有权, 谢萍, 牛亦农. 雄激素受体与PI3K/AKT通路相互作用机制在前列腺癌中的研究进展[J]. 首都医科大学学报, 2025, 46(2): 269-282.

Xiong Tianyu, Zhao Youquan, Xie Ping, Niu Yinong. Advances in research on the interaction mechanisms between androgen receptor and PI3K/AKT pathways in prostate cancer[J]. Journal of Capital Medical University, 2025, 46(2): 269-282.

参考文献

［1］Zheng R S, Chen R, Han B F, et al. Cancer incidence and mortality in China, 2022［J］. J Natl Cancer Cent, 2024, 46(3): 221－231.
［2］Westaby D, Fenor de La Maza M D L D, Paschalis A, et al. A new old target: androgen receptor signaling and advanced prostate cancer［J］. Annu Rev Pharmacol Toxicol, 2022, 62: 131－153.
［3］Choudhury A D. PTEN-PI3K pathway alterations in advanced prostate cancer and clinical implications［J］. Prostate, 2022, 82: S60-S72.
［4］Tilki D, van den Bergh R C N, Briers E, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer. Part Ⅱ-2024 update: treatment of relapsing and metastatic prostate cancer［J］. Eur Urol, 2024, 86(2): 164－182.
［5］ Abida W， Campbell D， Patnaik A， et al. Rucaparib for the treatment of metastatic castration-resistant prostate cancer associated with a DNA damage repair gene alteration: final results from the phase 2 TRITON2 study［J］. Eur Urol， 2023， 84(3)： 321－330.
［6］Crabb S J, Griffiths G, Marwood E, et al. Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: a randomized, placebo-controlled phase II trial (ProCAID)［J］. J Clin Oncol, 2021, 39(3): 190－201.
［7］George D J, Halabi S S, Healy P, et al. Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer［J］. Urol Oncol, 2020, 38(3): 79.e15－79.e22.
［8］Raith F, O'Donovan D H, Lemos C, et al. Addressing the reciprocal crosstalk between the AR and the PI3K/AKT/mTOR signaling pathways for prostate cancer treatment［J］. Int J Mol Sci, 2023, 24(3): 2289.
［9］Carver B S, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer［J］. Cancer Cell, 2011, 19(5): 575－586.
［10］Thomas C, Lamoureux F, Crafter C, et al. Synergistic targeting of PI3K/AKT pathway and androgen receptor axis significantly delays castration-resistant prostate cancer progression in vivo［J］. Mol Cancer Ther, 2013, 12(11): 2342－2355.
［11］Rathkopf D E, Larson S M, Anand A, et al. Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: phase 1/2 results and signaling pathway implications［J］. Cancer, 2015, 121(21): 3853－3861.
［12］Graham L, Banda K, Torres A, et al. A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer［J］. Invest New Drugs, 2018, 36(3): 458－467.
［13］Davey R A, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside［J］. Clin Biochem Rev, 2016, 37(1): 3－15.
［14］Lubahn D B, Brown T R, Simental J A, et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity［J］. Proc Natl Acad Sci U S A, 1989, 86(23): 9534－9538.
［15］Callewaert L, Van Tilborgh N, Claessens F. Interplay between two hormone-independent activation domains in the androgen receptor［J］. Cancer Res, 2006, 66(1): 543－553.
［16］Dehm S M, Regan K M, Schmidt L J, et al. Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion Independent prostate cancer cells［J］. Cancer Res, 2007, 67(20): 10067－10077.
［17］Shaffer P L, Jivan A, Dollins D E, et al. Structural basis of androgen receptor binding to selective androgen response elements［J］. Proc Natl Acad Sci U S A, 2004, 101(14): 4758－4763.
［18］Matias P M, Donner P, Coelho R, et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations［J］. J Biol Chem, 2000, 275(34): 26164－26171.
［19］Sack J S, Kish K F, Wang C, et al. Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone［J］. Proc Natl Acad Sci U S A, 2001, 98(9): 4904－4909.
［20］Smith D F, Toft D O. Minireview: the intersection of steroid receptors with molecular chaperones: observations and questions［J］. Mol Endocrinol, 2008, 22(10): 2229－2240.
［21］Zhou Z X, Sar M, Simental J A, et al. A ligand-dependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences［J］. J Biol Chem, 1994, 269(18): 13115－13123.
［22］Cutress M L, Whitaker H C, Mills I G, et al. Structural basis for the nuclear import of the human androgen receptor［J］. J Cell Sci, 2008, 121(Pt 7): 957－968.
［23］Santi D N E, Spaggiari G, Gilioli L, et al. Molecular basis of androgen action on human sexual desire［J］. Mol Cell Endocrinol, 2018, 467: 31－41.
［24］Shafi A A, Yen A E, Weigel N L. Androgen receptors in hormone-dependent and castration-resistant prostate cancer［J］. Pharmacol Ther, 2013, 140(3): 223－238.
［25］Parker C, Sartor O. Abiraterone and increased survival in metastatic prostate cancer［J］. N Engl J Med, 2011, 365(8): 767.
［26］Pandey S K, Sabharwal U, Tripathi S, et al. Androgen signaling in prostate cancer: when a friend turns foe［J］. Endocr Metab Immune Disord Drug Targets, 2025, 25(1): 37－56.
［27］Huggins C. Effect of orchiectomy and irradiation on cancer of the prostate［J］. Ann Surg, 1942, 115(6): 1192－1200.
［28］Desai K, McManus J M, Sharifi N. Hormonal therapy for prostate cancer［J］. Endocr Rev, 2021, 42(3): 354－373.
［29］Malek R, Wu S T, Serrano D, et al. ELIGANT: a phase 4, interventional, safety study of leuprorelin acetate (ELIGARD 􀅺) in Asian men with prostate cancer［J］. Transl Androl Urol, 2022, 11(2): 179－189.
［30］Matveev V, Gao X, Kopyltsov E, et al. PRIORITI: phase 4 study of triptorelin or active surveillance in high-risk prostate cancer［J］. Asia Pac J Clin Oncol, 2024, 20(6): 738－746.
［31］Devosv G, Tosco L, Baldewijns M, et al. ARNEO: a randomized phase II trial of neoadjuvant degarelix with or without apalutamide prior to radical prostatectomy for high-risk prostate cancer［J］. Eur Urol, 2023, 83(6): 508－518.
［32］Lorente D, Llacer C, Lozano R, et al. Prognostic score and benefit from abiraterone in first-line metastatic, castration-resistant prostate cancer［J］. Eur Urol, 2021, 80(5): 641－649.
［33］Yokomizo A, Shiota M, Morokuma F, et al. GnRH antagonist monotherapy versus a GnRH agonist plus bicalutamide for advanced hormone-sensitive prostate cancer; KYUCOG-1401［J］. Int J Urol, 2024, 31(4): 362－369.
［34］Colomba E, Jonas S F, Eymard J C, et al. A randomized, open-label, cross-over phase 2 trial of darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer: patient preference and cognitive function in ODENZA［J］. Eur Urol, 2024, 85(3): 274－282.
［35］Chowdhury S, Bjartell A, Agarwal N, et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer［J］. Ann Oncol, 2023, 34(5): 477－485.
［36］Attard G, Parker C, Eeles R A, et al. Prostate cancer［J］. Lancet, 2016, 387(10013): 70－82.
［37］Tietz K T, Dehm S M. Androgen receptor variants: RNA-based mechanisms and therapeutic targets［J］. Hum Mol Genet, 2020, 29(R1): R19-R26.
［38］Abida W, Cyrta J, Heller G, et al. Genomic correlates of clinical outcome in advanced prostate cancer［J］. Proc Natl Acad Sci U S A, 2019, 116(23): 11428－11436.
［39］Chen W S, Aggarwal R, Zhang L, et al. Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer［J］. Eur Urol, 2019, 76(5): 562－571.
［40］Ledet E M, Lilly M B, Sonpavde G, et al. Comprehensive analysis of AR alterations in circulating tumor DNA from patients with advanced prostate cancer［J］. Oncologist, 2020, 25(4): 327－333.
［41］Conteduca V, Wetterskog D, Sharabiani M T A, et al. Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study［J］. Ann Oncol, 2017, 28(7): 1508－1516.
［42］Zhai W， Sun Y， Guo C， et al. LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143－3p signals［J］. Cell Death Differ，2017，24(9)：1502－1517.
［43］Wang W X, Kong A A, Feng K L, et al. Exosomal miR-222－3p contributes to castration-resistant prostate cancer by activating mTOR signaling［J］. Cancer Sci, 2023, 114(11): 4252－4269.
［44］Zhang S Q, Meng X L, Zhang S, et al. Design, synthesis, and biological evaluation of androgen receptor (AR) antagonist-heat shock protein 90 (Hsp90) inhibitor conjugates for targeted therapy of castration-resistant prostate cancer［J］. J Med Chem, 2023, 66(7): 4784-4801.
［45］Wang L G, Johnson E M, Kinoshita Y, et al. Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex［J］. Cancer Res, 2008, 68(8): 2678－2688.
［46］Veldscholte J, Berrevoets C A, Ris-Stalpers C, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens［J］. J Steroid Biochem Mol Biol, 1992, 41(3/8): 665－669.
［47］Prekovic S，van Royen M E，Voet A R，et al. The effect of F877L and T878A mutations on androgen receptor response to enzalutamide［J］. Mol Cancer Ther，2016，15(7)：1702－1712.
［48］Bohl C E, Miller D D, Chen J Y, et al. Structural basis for accommodation of nonsteroidal ligands in the androgen receptor［J］. J Biol Chem, 2005, 280(45): 37747－37754.
［49］Lallous N, Volik S V, Awrey S, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients［J］. Genome Biol, 2016, 17: 10.
［50］Han D, Labaf M, Zhao Y W, et al. Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs［J］. J Clin Invest, 2024, 134(11): e168649.
［51］Dehm S M, Schmidt L J, Heemers H V, et al. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance［J］. Cancer Res, 2008, 68(13): 5469－5477.
［52］Hu R, Dunn T A, Wei S Z, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer［J］. Cancer Res, 2009, 69(1): 16－22.
［53］Sharp A, Coleman I, Yuan W, et al. Androgen receptor splice variant－7 expression emerges with castration resistance in prostate cancer［J］. J Clin Invest, 2019, 129(1): 192－208.
［54］Antonarakis E S, Lu C X, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer［J］. N Engl J Med, 2014, 371(11): 1028－1038.
［55］Armstrong A J, Halabi S S, Luo J, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study［J］. J Clin Oncol, 2019, 37(13): 1120－1129.
［56］Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signalling: the path to discovery and understanding［J］. Nat Rev Mol Cell Biol, 2012, 13(3): 195－203.
［57］Engelman J A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations［J］. Nat Rev Cancer, 2009, 9(8): 550－562.
［58］Vanhaesebroeck B, Leevers S J, Panayotou G, et al. Phosphoinositide 3-kinases: a conserved family of signal transducers［J］. Trends Biochem Sci, 1997, 22(7): 267－272.
［59］Vanhaesebroeck B, Welham M J, Kotani K, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes［J］. Proc Natl Acad Sci U S A, 1997, 94(9): 4330－4335.
［60］Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, et al. The emerging mechanisms of isoform-specific PI3K signalling［J］. Nat Rev Mol Cell Biol, 2010, 11(5): 329－341.
［61］He Y, Sun M M, Zhang G G, et al. Targeting PI3K/Akt signal transduction for cancer therapy［J］. Signal Transduct Target Ther, 2021, 6(1): 425.
［62］Spangle J M, Roberts T M. Epigenetic regulation of RTK signaling［J］. J Mol Med (Berl), 2017, 95(8): 791－798.
［63］Sangwan V, Park M. Receptor tyrosine kinases: role in cancer progression［J］. Curr Oncol, 2006, 13(5): 191－193.
［64］Tamada M， Shi J， Bourdot K S， et al. Toll receptors remodel epithelia by directing planar-polarized Src and PI3K activity［J］. Dev Cell，2021，56(11)：1589－1602.e9.
［65］Aiba Y, Kameyama M G I, Yamazaki T, et al. Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase［J］. Blood, 2008, 111(3): 1497－1503.
［66］Wang R, Qu Z, Lv Y, et al. Important roles of PI3K/AKT signaling pathway and relevant inhibitors in prostate cancer progression［J］. Cancer Med, 2024, 13(21): e70354.
［67］Staal S P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma［J］. Proc Natl Acad Sci U S A, 1987, 84(14): 5034－5037.
［68］Degan S E, Gelman I H. Emerging roles for AKT isoform preference in cancer progression pathways［J］. Mol Cancer Res, 2021, 19(8): 1251－1257.
［69］Alessi D R, Andjelkovic M, Caudwell B, et al. Mechanism of activation of protein kinase B by insulin and IGF-1［J］. EMBO J, 1996, 15(23): 6541－6551.
［70］Alessi D R, James S R, Downes C P, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha［J］. Curr Biol, 1997, 7(4): 261－269.
［71］Chen Y， Jiao D， He H， et al. Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation［J］. Redox Biol， 2023， 67： 102872.
［72］Manning B D, Cantley L C. AKT/PKB signaling: navigating downstream［J］. Cell, 2007, 129(7): 1261－1274.
［73］Rathmell J C, Fox C J, Plas D R, et al. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival［J］. Mol Cell Biol, 2003, 23(20): 7315－7328.
［74］Berwick D C, Hers I, Heesom K J, et al. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes［J］. J Biol Chem, 2002, 277(37): 33895－33900.
［75］Düvel K, Yecies J L, Menon S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1［J］. Mol Cell, 2010, 39(2): 171－183.
［76］Li J Y, Ren K K, Zhang W J, et al. Human amniotic mesenchymal stem cells and their paracrine factors promote wound healing by inhibiting heat stress-induced skin cell apoptosis and enhancing their proliferation through activating PI3K/AKT signaling pathway［J］. Stem Cell Res Ther, 2019, 10(1): 247.
［77］Chibaya L， Karim B， Zhang H， et al. Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis［J］. Proc Natl Acad Sci U S A， 2021， 118(4)： e2003193118.
［78］Yang C, Jin X, Liu X C, et al. TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs［J］. Cell Death Dis, 2023, 14(1): 47.
［79］Zhao Z B, Gao J, Li C L, et al. Reactive oxygen species induce endothelial differentiation of liver cancer stem-like sphere cells through the activation of Akt/IKK signaling pathway［J］. Oxid Med Cell Longev, 2020, 2020: 1621687.
［80］Song F， Wang C G， Wang T L， et al. Enhancement of gemcitabine sensitivity in intrahepatic cholangiocarcinoma through saikosaponin—a mediated modulation of the p-AKT/BCL-6/ABCA1 axis［J］. Phytomedicine， 2024， 133： 155944.
［81］Liu Y， Zhang T， Deng J， et al. The cytotoxicity of γδT cells in non-small cell lung cancer mediated via coordination of the BCL-2 and AKT pathways［J］. Oncogene，2023，42(49)：3648－3654.
［82］Rouzi K, Altay A, Bouatia M, et al. Novel isoniazid-hydrazone derivatives induce cell growth inhibition, cell cycle arrest and apoptosis via mitochondria-dependent caspase activation and PI3K/AKT inhibition［J］. Bioorg Chem, 2024, 150: 107563.
［83］Gonçalves J, Pinto S, Carmo F, et al. Additive cytotoxic and colony-formation inhibitory effects of aspirin and metformin on PI3KCA-mutant colorectal cancer cells［J］. Int J Mol Sci, 2024, 25(10): 5381.
［84］Gerstung M, Jolly C, Leshchiner I, et al. The evolutionary history of 2,658 cancers［J］. Nature, 2020, 578(7793): 122－128.
［85］Tsolakos N, Durrant T N, Chessa T, et al. Quantitation of class IA PI3Ks in mice reveals p110-free-p85s and isoform-selective subunit associations and recruitment to receptors［J］. Proc Natl Acad Sci U S A, 2018, 115(48): 12176－12181.
［86］Mekhamer A M, Saied M H, Elneily D A E, et al. Targeted sequencing of HER2-Positive breast cancer mutations revealed a potential association between PIK3CA and trastuzumab resistance［J］. Asian Pac J Cancer Prev, 2024, 25(11): 4051－4059.
［87］Dey N, Leyland-Jones B, De P. MYC-xing it up with PIK3CA mutation and resistance to PI3K inhibitors: summit of two giants in breast cancers［J］. Am J Cancer Res, 2015, 5(1): 1－19.
［88］Liu X H, Mei W X, Zhang P F, et al. PIK3CA mutation as an acquired resistance driver to EGFR-TKIs in non-small cell lung cancer: clinical challenges and opportunities［J］. Pharmacol Res, 2024, 202: 107123.
［89］Zhang H, Zhang L, He Y, et al. PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer［J］. Cancer Lett, 2024, 598: 217112.
［90］Candido S, Salemi R, Piccinin S, et al. The PIK3CA H1047R mutation confers resistance to BRAF and MEK inhibitors in a375 melanoma cells through the cross-activation of MAPK and PI3K-Akt pathways［J］. Pharmaceutics, 2022, 14(3): 590.
［91］Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer［J］. Science, 1997, 275(5308): 1943－1947.
［92］Lee Y R, Chen M, Pandolfi P P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects［J］. Nat Rev Mol Cell Biol, 2018, 19(9): 547－562.
［93］Turnham D J, Bullock N, Dass M S, et al. The PTEN conundrum: how to target PTEN-Deficient prostate cancer［J］. Cells, 2020, 9(11): 2342.
［94］Wang X J, Trotman L C, Koppie T, et al. NEDD4－1 is a proto-oncogenic ubiquitin ligase for PTEN［J］. Cell, 2007, 128(1): 129－139.
［95］Xie P, Peng Z Q, Chen Y J, et al. Neddylation of PTEN regulates its nuclear import and promotes tumor development［J］. Cell Res, 2021, 31(3): 291－311.
［96］Lee Y R, Chen M, Lee J D, et al. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway［J］. Science, 2019, 364(6441): eaau0159.
［97］Lin Y X, Wang Y, Ding J X, et al. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models［J］. Sci Transl Med, 2021, 13(599): eaba9772.
［98］Kim Y, Choi J, Kim E H, et al. Design of PD-L1-Targeted lipid nanoparticles to turn on PTEN for efficient cancer therapy［J］. Adv Sci, 2024, 11(22): e2309917.
［99］Tserga A， Chatziandreou I， Michalopoulos N V， et al. Mutation of genes of the PI3K/AKT pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness［J］. Virchows Arch， 2016， 469(1)： 35－43.
［100］Shimoi T, Hashimoto J, Sudo K, et al. Hotspot mutation profiles of AKT1 in Asian women with breast and endometrial cancers［J］. BMC Cancer, 2021, 21(1): 1131.
［101］Askham J M, Platt F, Chambers P A, et al. AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K［J］. Oncogene, 2010, 29(1): 150－155.
［102］El Ahanidi H, El Azzouzi M, Arrouchi H, et al. AKT1 and PIK3CA activating mutations in Moroccan bladder cancer patients' biopsies and matched urine［J］. Pan Afr Med J, 2022, 41: 59.
［103］Hechtman J F， Sadowska J， Huse J T， et al. AKT1 E17K in colorectal carcinoma is associated with BRAF V600E but not MSI-H status: a clinicopathologic comparison to PIK3CA helical and kinase domain mutants［J］. Mol Cancer Res， 2015， 13(6)：1003－1008.
［104］Carpten J D, Faber A L, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer［J］. Nature, 2007, 448(7152): 439－444.
［105］Landgraf K E, Pilling C, Falke J J. Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain［J］. Biochemistry, 2008, 47(47): 12260－12269.
［106］Hyman D M, Smyth L M, Donoghue M T A, et al. AKT inhibition in solid tumors with AKT1 mutations［J］. J Clin Oncol, 2017, 35(20): 2251－2259.
［107］Kalinsky K, Hong F X, McCourt C K, et al. Effect of capivasertib in patients with an AKT1 E17K-mutated tumor: NCI-MATCH subprotocol EAY131-Y nonrandomized trial［J］. JAMA Oncol, 2021, 7(2): 271－278.
［108］Jamroze A, Chatta G, Tang D G. Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance［J］. Cancer Lett, 2021, 518: 1－9.
［109］Hashemi M, Taheriazam A, Daneii P, et al. Targeting PI3K/Akt signaling in prostate cancer therapy［J］. J Cell Commun Signal, 2023, 17(3): 423－443.
［110］Converse A, Thomas P. Androgens promote vascular endothelial cell proliferation through activation of a ZIP9-dependent inhibitory G protein/PI3K-Akt/Erk/cyclin D1 pathway［J］. Mol Cell Endocrinol, 2021, 538: 111461.
［111］Darshit B S, Ramanathan M. Activation of AKT1/GSK-3β/β-Catenin-TRIM11/survivin pathway by novel GSK-3β inhibitor promotes neuron cell survival: study in differentiated SH-SY5Y cells in OGD model［J］. Mol Neurobiol, 2016, 53(10): 6716－6729.
［112］Nyquist M D, Corella A, Burns J, et al. Exploiting AR-regulated drug transport to induce sensitivity to the survivin inhibitor YM155［J］. Mol Cancer Res, 2017, 15(5): 521－531.
［113］Liu X, Sun C F, Zou K X, et al. Novel PGK1 determines SKP2-dependent AR stability and reprograms granular cell glucose metabolism facilitating ovulation dysfunction［J］. EBioMedicine, 2020, 61: 103058.
［114］Fontana F, Giannitti G, Marchesi S, et al. The PI3K/Akt pathway and glucose metabolism: a dangerous liaison in cancer［J］. Int J Biol Sci, 2024, 20(8): 3113－3125.
［115］Zhao S H, Cheng L, Shi Y, et al. MIEF2 reprograms lipid metabolism to drive progression of ovarian cancer through ROS/AKT/mTOR signaling pathway［J］. Cell Death Dis, 2021, 12(1): 18.
［116］Berchuck J E, Adib E, Abou Alaiwi S, et al. The prostate cancer androgen receptor cistrome in African American men associates with upregulation of lipid metabolism and immune response［J］. Cancer Res, 2022, 82(16): 2848－2859.
［117］Audet-Walsh É, Dufour C R, Yee T, et al. Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer［J］. Genes Dev, 2017, 31(12): 1228－1242.
［118］Ren Q N, Zhang H, Sun C Y, et al. Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis［J］. Hepatology, 2022, 75(5): 1123－1138.
［119］Castoria G, Lombardi M, Barone M V, et al. Androgen-stimulated DNA synthesis and cytoskeletal changes in fibroblasts by a nontranscriptional receptor action［J］. J Cell Biol, 2003, 161(3): 547－556.
［120］Mukhopadhyay C， Yang C， Xu L， et al. G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer［J］. Nat Commun， 2021， 12(1)： 6662.
［121］An J, Wang C J, Deng Y B, et al. Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants［J］. Cell Rep, 2014, 6(4): 657－669.
［122］Barbieri C E, Baca S C, Lawrence M S, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and Med12 mutations in prostate cancer［J］. Nat Genet, 2012, 44(6): 685－689.
［123］Blattner M, Lee D J, O'Reilly C, et al. SPOP mutations in prostate cancer across demographically diverse patient cohorts［J］. Neoplasia, 2014, 16(1): 14－20.
［124］Blattner M, Liu D, Robinson B D, et al. SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling［J］. Cancer Cell, 2017, 31(3): 436－451.
［125］Jiang Q, Zheng N, Bu L, et al. SPOP-mediated ubiquitination and degradation of PDK1 suppresses AKT kinase activity and oncogenic functions［J］. Mol Cancer, 2021, 20(1): 100.
［126］Mulholland D J, Tran L M, Li Y F, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth［J］. Cancer Cell, 2011, 19(6): 792－804.
［127］Lee S H, Johnson D, Luong R, et al. Crosstalking between androgen and PI3K/AKT signaling pathways in prostate cancer cells［J］. J Biol Chem, 2015, 290(5): 2759－2768.
［128］Sheflin L, Keegan B, Zhang W, et al. Inhibiting proteasomes in human HepG2 and LNCaP cells increases endogenous androgen receptor levels［J］. Biochem Biophys Res Commun, 2000, 276(1): 144－150.
［129］Lin H K, Yeh S, Kang H Y, et al. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor［J］. Proc Natl Acad Sci U S A, 2001, 98(13): 7200－7205.
［130］Lin H K, Wang L, Hu Y C, et al. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase［J］. EMBO J, 2002, 21(15): 4037－4048.
［131］Kong L, Yuan Q, Zhu H R, et al. The suppression of prostate LNCaP cancer cells growth by selenium nanoparticles through Akt/Mdm2/AR controlled apoptosis［J］. Biomaterials, 2011, 32(27): 6515－6522.
［132］Kwon D H， Eom G H， Ko J H， et al. MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification［J］. Nat Commun， 2016， 7： 10492.
［133］Zhao Y, Tindall D J, Huang H J. Modulation of androgen receptor by FOXA1 and FOXO1 factors in prostate cancer［J］. Int J Biol Sci, 2014, 10(6): 614－619.
［134］Brunet A, Bonni A, Zigmond M J, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor［J］. Cell, 1999, 96(6): 857－868.
［135］Liu P, Li S W, Gan L, et al. A transcription-independent function of FOXO1 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells［J］. Cancer Res, 2008, 68(24): 10290－10299.
［136］Bian S, Ni W, Zhou L, et al. Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization［J］. Cell Death Differ, 2024, 31(9): 1202－1218.
［137］Hsu F N, Chen M C, Chiang M C, et al. Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5［J］. J Biol Chem, 2011, 286(38): 33141－33149.
［138］Lindqvist J, Imanishi S Y, Torvaldson E, et al. Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells［J］. Mol Biol Cell, 2015, 26(11): 1971－1984.
［139］Kao W H, Chiu K Y, Tsai S C S, et al. PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation［J］. Biochim Biophys Acta Mol Basis Dis, 2025, 1871(2): 167568.
［140］Newton A C, Trotman L C. Turning off AKT: PHLPP as a drug target［J］. Annu Rev Pharmacol Toxicol, 2014, 54: 537－558.
［141］Pei H D, Li L, Fridley B L, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt［J］. Cancer Cell, 2009, 16(3): 259－266.
［142］Xiong X Y, Zhang S Y, Zhu W Z, et al. Androgen-ablative therapies inducing CXCL8 regulates mTORC1/SREBP2-dependent cholesterol biosynthesis to support progression of androgen receptor negative prostate cancer cells［J］. Oncogene, 2024, 43(47): 3456－3468.
［143］Taylor B S, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer［J］. Cancer Cell, 2010, 18(1): 11－22.
［144］Armstrong A J, Halabi S S, Healy P, et al. Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer［J］. Eur J Cancer, 2017, 81: 228－236.
［145］Rescigno P, Porta N, Finneran L, et al. Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: results from the randomized phase II RE-AKT trial［J］. Eur J Cancer, 2024, 205: 114103.
［146］Chow H, Ghosh P M, deVere White R, et al. A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer［J］. Cancer, 2016, 122(12): 1897－1904.
［147］Tortorella E, Giantulli S, Sciarra A, et al. AR and PI3K/AKT in prostate cancer: a tale of two interconnected pathways［J］. Int J Mol Sci, 2023, 24(3): 2046.
［148］Sweeney C J, Percent I J, Babu S, et al. Phase Ib/II study of enzalutamide with samotolisib (LY3023414) or placebo in patients with metastatic castration-resistant prostate cancer［J］. Clin Cancer Res, 2022, 28(11): 2237－2247.
［149］Sweeney C, Bracarda S, Sternberg C N, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial［J］. Lancet, 2021, 398(10295): 131－142.
［150］Massard C, Chi K N, Castellano D, et al. Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer.［J］ Eur J Cancer，2017，76：36－44.
［151］Sarker D, Dawson N A, Aparicio A M, et al. A phase I, open-label, dose-finding study of GSK2636771, a PI3Kβ inhibitor, administered with enzalutamide in patients with metastatic castration-resistant prostate cancer［J］. Clin Cancer Res，2021，27：5248－5257.
［152］de Bono J S, De Giorgi U, Rodrigues D N, et al. Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss［J］. Clin Cancer Res，2019，25：928－936.
［153］Shore N, Mellado B, Shah S, et al. A phase I study of capivasertib in combination with abiraterone acetate in patients with metastatic castration-resistant prostate cancer［J］. Clin Genitourin Cancer，2023，21：278－285.
［154］Kolinsky M P, Rescigno P, Bianchini D, et al. A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer［J］. Ann Oncol，2020，31：619－625.
［155］Nakabayashi M, Werner L, Courtney K D, et al. Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer［J］. BJU Int，2012，110：1729－1735.
［156］Zhao J L, Antonarakis E S, Cheng H H, et al. Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC)［J］. Br J Cancer，2024，130：53－62.

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