Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of autophagy in prostate cancer and prostatic diseases: a new therapeutic strategy

Prostate Cancer and Prostatic Diseases (2024)Cite this article

Subjects

Abstract

Background

Autophagy is a well-conserved catabolic process that plays a key role in cell homeostasis. In the prostate, defective autophagy has been implicated in the genesis and progression of several pathological conditions.

Aim

The present review explored the autophagy pathway in prostate-related dysfunctions, focusing on prostate cancer (PCa), benign prostatic hyperplasia (BPH) and prostatitis.

Results

Impaired autophagy activity has been shown in animal models of BPH and prostatitis. Moreover, autophagy activation by specific and non-specific drugs improved both conditions in pre-clinical studies. Conversely, the efficacy of autophagy inducers in PCa remains controversial, depending on intrinsic PCa characteristics and stage of progression. Intriguingly, autophagy inhibitors have shown beneficial effects in PCa suppression or even to overcome chemotherapy resistance. However, there are still open questions regarding the upstream mechanisms by which autophagy is deregulated in the prostate and the exact role of autophagy in PCa. The lack of specificity and increased toxicity associated with the currently autophagy inhibitors limits its use clinically, reflecting in reduced number of clinical data.

Conclusion

New therapeutic strategies to treat prostatic diseases involving new autophagy modulators, combination therapy and new drug formulations should be explored. Understanding the autophagy signaling in each prostatic disease is crucial to determine the best pharmacological approach.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Schematic representation of the pathways involved in autophagy-related prostatic diseases.
Fig. 2: Overview of autophagy-specific drugs in ameliorating prostatic diseases.
Fig. 3: Overview of autophagy-non-specific drugs action in prostatic diseases.

Similar content being viewed by others

References

  1. Martins WK, Silva M, Pandey K, Maejima I, Ramalho E, Olivon VC, et al. Autophagy-targeted therapy to modulate age-related diseases: success, pitfalls, and new directions. Curr Res Pharm Drug Discov. 2021;2:100033.

    Article  Google Scholar 

  2. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147:728–41.

    Article  CAS  PubMed  Google Scholar 

  3. Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020;19:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Liu WJ, Ye L, Huang WF, Guo LJ, Xu ZG, Wu HL, et al. p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation. Cell Mol Biol Let. 2016;21:29.

    Article  Google Scholar 

  5. Boutouja F, Stiehm CM, Platta HW. mTOR: a cellular regulator interface in health and disease. Cells. 2019;8:18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gupta P, Kumar N, Garg M. Emerging roles of autophagy in the development and treatment of urothelial carcinoma of the bladder. Expert Opin Ther Targets. 2021;25:787–97.

    Article  CAS  PubMed  Google Scholar 

  7. Liu RF, Fu G, Li J, Yang YF, Wang XG, Bai PD, et al. Roles of autophagy in androgen-induced benign prostatic hyperplasia in castrated rats. Expert Opin Ther Targets. 2018;15:2703–10.

    CAS  Google Scholar 

  8. Oh SH, Lee DW, Choi YB, Lee Y, Ju J. Measurement of autophagy flux in benign prostatic hyperplasia in vitro. Prostate Int. 2020;8:70–77.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lu J, Su Y, Chen X, Chen Y, Luo P, Lin F, et al. Rapamycin‑induced autophagy attenuates hormone‑imbalance‑induced chronic non‑bacterial prostatitis in rats via the inhibition of NLRP3 inflammasome‑mediated inflammation. Mol Med Rep. 2019;19:221–30.

    CAS  PubMed  Google Scholar 

  10. McIlwain DW, Zoetemelk M, Myers JD, Edwards M, Snider B, Jerde TJ. Coordinated induction of cell survival signaling in the inflamed microenvironment of the prostate. Prostate. 2016;76:722–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang J, Zhang X, Cai Z, Li N, Li H. The lifetime risk and prognosis of chronic prostatitis/chronic pelvic pain syndrome in the middle-aged Chinese males. Am J Mens Health. 2019;13:1557988319865380.

  12. Su Y, Lu J, Chen X, Liang C, Luo P, Qin C, et al. Rapamycin alleviates hormone imbalance-induced chronic nonbacterial inflammation in rat prostate through activating autophagy via the mTOR/ULK1/ATG13 signaling pathway. Inflammation. 2018;41:1384–95.

    Article  CAS  PubMed  Google Scholar 

  13. Zhu Y, Yin Q, Wei D, Yang Z, Du Y, Ma Y. Autophagy in male reproduction. Syst Biol Reprod Med. 2019;65:265–72.

    Article  PubMed  Google Scholar 

  14. Kuma A, Komatsu M, Mizushima N. Autophagy-monitoring and autophagy-deficient mice. Autophagy. 2017;13:1619–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013;13:722–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Silva JAF, Bruni-Cardoso A, Augusto TM, Damas-Souza D, Barbosa G, Felisbino SL, et al. Macrophage roles in the clearance of apoptotic cells and control of inflammation in the prostate gland after castration. Prostate. 2018;78:95–103.

    Article  CAS  PubMed  Google Scholar 

  17. Clemens JQ, Meenan RT, O’Keeffe Rosetti MC, Kimes T, Calhoun E. Prevalence of and risk factors for prostatitis: population based assessment using physician assigned diagnoses. J Urol. 2007;178:1333–7.

    Article  PubMed  Google Scholar 

  18. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469:323–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pei F, Wang HS, Chen Z, Zhang L. Autophagy regulates odontoblast differentiation by suppressing NF-kappaB activation in an inflammatory environment. Cell Death Dis. 2016;7:e2122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kashyap M, Pore S, Wang Z, Gingrich J, Yoshimura N, Tyagi P. Inflammasomes are important mediators of prostatic inflammation associated with BPH. J Inflamm (Lond). 2015;12:37.

  21. Choi S, Shin H, Song H, Lim H. Suppression of autophagic activation in the mouse uterus by estrogen and progesterone. J Endocrinol. 2014;221:39–50.

    Article  CAS  PubMed  Google Scholar 

  22. Ng M, Baradhi KM. Benign prostatic hyperplasia. StatPearls (2023).

  23. De Nunzio C, Giglio S, Baldassarri V, Cirombella R, Mallel G, Nacchia A, et al. Impairment of autophagy may represent the molecular mechanism behind the relationship between obesity and inflammation in patients with BPH and LUTS. Minerva Urol Nephrol. 2021;73:631–7.

    Article  PubMed  Google Scholar 

  24. De Nunzio C, Giglio S, Stoppacciaro A, Gacci M, Cirombella R, Luciani E, et al. Autophagy deactivation is associated with severe prostatic inflammation in patients with lower urinary tract symptoms and benign prostatic hyperplasia. Oncotarget. 2017;8:50904–10.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lesovaya E, Kirsanov K, Antoshina E, Trukhanova L, Gorkova T, Shipaeva EV, et al. Rapatar, a nanoformulation of rapamycin, decreases chemically-induced benign prostate hyperplasia in rats. Oncotarget. 2015;6:9718–27.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jiang MY, Han ZD, Li W, Yue F, Ye J, Li B, et al. Mitochondrion-associated protein peroxiredoxin 3 promotes benign prostatic hyperplasia through autophagy suppression and pyroptosis activation. Oncotarget. 2017;8:80295–302.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Michiels CF, Fransen P, De Munck DG, De Munck D, De Meyer G, Martinet W. Defective autophagy in vascular smooth muscle cells alters contractility and Ca(2)(+) homeostasis in mice. Am J Physiol Heart Circ Physiol. 2015;308:557–67.

    Article  Google Scholar 

  28. McCarthy CG, Wenceslau CF, Calmasini FB, Klee NS, Brands MW, Joe B, et al. Reconstitution of autophagy ameliorates vascular function and arterial stiffening in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2019;317:1013–27.

    Article  Google Scholar 

  29. Li M, Yang X, Wang H, Xu E, Xi Z. Inhibition of androgen induces autophagy in benign prostate epithelial cells. Int J Urol. 2014;21:195–9.

    Article  CAS  PubMed  Google Scholar 

  30. Yang BY, Jiang CY, Dai CY, Zhao RZ, Wang XJ, Zhu YP, et al. 5-ARI induces autophagy of prostate epithelial cells through suppressing IGF-1 expression in prostate fibroblast. Cell Prolif. 2019;52:e12590.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nickel JC, Gilling P, Tammela TL, Morrill B, Wilson T, Rittmaster RS. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int. 2011;108:388–94.

    Article  CAS  PubMed  Google Scholar 

  32. Rawla P. Epidemiology of prostate cancer. World J Oncol. 2019;10:63–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Turner LS, Cheng JCM, Beckham TH, Keane TE, Norris JS, Liu X. Autophagy is increased in prostate cancer cells overexpressing acid ceramidase and enhances resistance to C6 ceramide. Prostate Cancer Prostatic Dis. 2011;14:30–7.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang B, Liu L. Autophagy is a double-edged sword in the therapy of colorectal cancer. Oncol Lett. 2021;21:378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu C, Xu P, Chen D, Fan X, Xu Y, Li M, et al. Roles of autophagy-related genes Beclin-1 and LC3 in the development and progression of prostate cancer and benign prostatic hyperplasia. Biomed Rep. 2013;1:855–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Aita VM, Liang XH, Murty VV, Pincus D, Yu W, Cayanis E, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59:59–65.

    Article  CAS  PubMed  Google Scholar 

  37. White E, Di Paola RS. The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 2009;15:5308–16.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ariosa AR, Lahiri V, Lei Y, Yang Y, Yin Z, Zhang Z, et al. A perspective on the role of autophagy in cancer. Biochim Biophys Acta Mol Basis Dis. 2021;1867:166262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pelekanou V, Castanas E. Androgen control in prostate cancer. J Cell Biochem. 2016;117:2224–34.

    Article  CAS  PubMed  Google Scholar 

  40. Li M, Jiang X, Liu D, Na Y, Gao GF, Xi Z. Autophagy protects LNCaP cell under androgen deprivation conditions. Autophagy. 2008;4:54–60.

    Article  CAS  PubMed  Google Scholar 

  41. Hu F, Zhao Y, Yu Y, Fang J, Cui R, Liu ZQ, et al. Docetaxel-mediated autophagy promotes chemoresistance in castration-resistant prostate cancer cells by inhibiting STAT3. Cancer Lett. 2018;416:24–30.

    Article  CAS  PubMed  Google Scholar 

  42. Yu Y, Yang FH, Zhang WT, Guo Y, Ye L, Yao XD. Mesenchymal stem cells desensitize castration-resistant prostate cancer to docetaxel chemotherapy via inducing TGF-beta1-mediated cell autophagy. Cell Biosci. 2021;11:7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu R, Zeng Y, Lei Z, Wang L, Yang H, Liu Z, et al. JAK/STAT3 signaling is required for TGF-beta-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol. 2014;44:1643–51.

    Article  CAS  PubMed  Google Scholar 

  44. O’Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, Gallagher WM, et al. Characterization and manipulation of docetaxel resistant prostate cancer cell lines. Mol Cancer. 2011;10:126.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chang P, Wang T, Chang YC, Chu C, Lee C, Hsu HW, et al. Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. PloS ONE. 2014;9:e88556.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Rodríguez-Berriguete G, Prieto A, Fraile B, Bouraoui Y, De Bethencourt FR, Martinez-Onsurbe P, et al. Relationship between IL-6/ERK and NF-kappaB: a study in normal and pathological human prostate gland. Eur Cytokine Netw. 2010;21:241–50.

    PubMed  Google Scholar 

  47. Wise GJ, Marella VK, Talluri G, Shirazian D. Cytokine variations in patients with hormone treated prostate cancer. J Urol. 2000;164:722–5.

    Article  CAS  PubMed  Google Scholar 

  48. Mahon KL, Henshall SM, Sutherland RL, Horvath LG. Pathways of chemotherapy resistance in castration-resistant prostate cancer. Endocr Relat Cancer. 2011;18:103–23.

    Article  Google Scholar 

  49. Cristofani R, Montagnani Marelli M, Cicardi ME, Fontana F, Marzagalli M, Limonta P, et al. Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells. Cell Death Dis. 2018;9:889.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Qiao Y, Choi JE, Tien JC, Simko SA, Rajendiran T, Vo JN, et al. Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer. Nat Cancer. 2021;2:978–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lasorsa F, di Meo NA, Rutigliano M, Ferro M, Terracciano D, Tataru OS, et al. Emerging hallmarks of metabolic reprogramming in prostate cancer. Int J Mol Sci. 2023;24:910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. di Meo NA, Lasorsa F, Rutigliano M, Milella M, Ferro M, Battaglia M, et al. The dark side of lipid metabolism in prostate and renal carcinoma: novel insights into molecular diagnostic and biomarker discovery. Expert Rev Mol Diagn. 2023;23:297–313.

    Article  PubMed  Google Scholar 

  53. Loizzo D, Pandolfo SD, Rofers D, Cerrato C, di Meio NA, Autorino R, et al. Novel insights into autophagy and prostate cancer: a comprehensive review. Int J Mol Sci. 2022;23:3826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Strohecker AM, Guo JU, Karsli-Uzunbas G, Price SM, Chen GJ, Mathew R, et al. Autophagy sustains mitochondrial glutamine metabolism and growth of Braf600E-driven lung tumors. Cancer Discov. 2013;3:1272–85.

    Article  CAS  PubMed  Google Scholar 

  55. Grossi V, Lucarelli G, Forte G, Peserico A, Matrone A, Germani A, et al. Loss of STK11 expression is an early event in prostate carginogenesis and predicts therapeutic response to targeted therapy against MAPK/p38. Autophagy. 2015;11:2102–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Roudsari N, Lashgari N, Momtaz S, Abaft S, Jamali F, Safaiepour P, et al. Inhibitors of the PI3K/Akt/mTOR pathway in prostate cancer chemoprevention and intervention. Pharmaceutics. 2021;13:1195.

  57. Wang Y, Mikhailova M, Bose S, Pan CX, deVere Whithe RW, Ghosh PM. Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene. 2008;27:7106–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ghosh PM, Malik SN, Bedolla RG, Wang Y, Mikhailova M, Prihoda TJ, et al. Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocr Relat Cancer. 2005;12:119–34.

    Article  CAS  PubMed  Google Scholar 

  59. Armstrong AJ, Netto GJ, Rudek MA, Halabi S, Wood DP, Creel PA, et al. A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. Clin Cancer Res. 2010;16:3057–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Farrow JM, Yang JC, Evans CP. Autophagy as a modulator and target in prostate cancer. Nat Rev Urol. 2014;11:508–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004;6:1221–8.

    Article  CAS  PubMed  Google Scholar 

  62. Baspinar S, Bircan S, Orhan H, Kapucuoglu N, Bozkurt KK. The relation of beclin 1 and bcl-2 expressions in high grade prostatic intraepithelial neoplasia and prostate adenocarcinoma: a tissue microarray study. Pathol Res Pr. 2014;210:412–8.

    Article  CAS  Google Scholar 

  63. Kim KY, Yun UJ, Yeom SH, Kim SC, Lee HJ, Ahn SC, et al. Inhibition of autophagy promotes hemistepsin a-induced apoptosis via reactive oxygen species-mediated AMPK-dependent signaling in human prostate cancer cells. Biomolecules. 2021;11:1806.

  64. Tan Q, Joshua AM, Wang M, Bristow RG, Wouters BG, Allen CJ, et al. Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity. Cancer Chemother Pharm. 2017;79:959–69.

    Article  CAS  Google Scholar 

  65. Hansen AR, Tannock IF, Templeton A, Chen E, Evans A, Knox J, et al. Pantoprazole affecting docetaxel resistance pathways via autophagy (PANDORA): phase II trial of high dose pantoprazole (autophagy inhibitor) with docetaxel in metastatic castration-resistant prostate cancer (mCRPC). Oncologist. 2019;24:1188–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen Z, Jiang Q, Zhu P, Chen Y, Xie X, Du Z, et al. NPRL2 enhances autophagy and the resistance to Everolimus in castration-resistant prostate cancer. Prostate. 2019;79:44–53.

    Article  CAS  PubMed  Google Scholar 

  67. Cao C, Subhawong T, Albert JM, Kim KW, Geng L, Sekhar KR, et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 2006;66:10040–7.

    Article  CAS  PubMed  Google Scholar 

  68. Templeton AJ, Dutoit V, Cathomas R, Rothermundt C, Bärtschi D, Droge C, et al. Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol. 2013;64:150–8.

    Article  CAS  PubMed  Google Scholar 

  69. George DJ, Halabi S, Healy P, Jonasch D, Anand M, Rasmussen J, et al. Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer. Urol Oncol. 2020;38:e15–e22.

    Article  Google Scholar 

  70. Rathkopf DE, Larson SM, Anand A, Morris MJ, Slovin SF, Shaffer DR, et al. Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: Phase 1/2 results and signaling pathway implications. Cancer. 2015;121:3853–61.

    Article  CAS  PubMed  Google Scholar 

  71. Vaishampayan U, Shevrin D, Stein M, Heilbrun L, Land S, Stark K, et al. Phase II trial of carboplatin, everolimus, and prednisone in metastatic castration-resistant prostate cancer pretreated with docetaxel chemotherapy: a prostate cancer clinical trial consortium study. Urology. 2015;86:1206–11.

    Article  PubMed  Google Scholar 

  72. Koshkin VS, Mir MV, Barata P, Gul A, Gupta R, Stephenson AJ, et al. Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer. Invest N. Drugs. 2019;37:559–66.

    Article  CAS  Google Scholar 

  73. Zedan MM, Mansour AK, Bakr AA, Sobh MA, Khodadadi H, Salles EL, et al. Effect of everolimus versus bone marrow-derived stem cells on glomerular injury in a rat model of glomerulonephritis: a preventive, predictive and personalized implication. Int J Mol Sci. 2021;23:344.

  74. Armstrong AJ, Shen T, Halabi S, Kemeny G, Bitting RL, Kartcheske P, et al. A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer. Clin Genitourin Cancer. 2013;11:397–406.

    Article  PubMed  Google Scholar 

  75. Kruczek K, Ratterman M, Tolzien K, Sulo S, Lestingi TM, Nabhan C. A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naive castration-resistant prostate cancer. Br J Cancer. 2013;109:1711–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. McHugh DJ, Chudow J, DeNunzio M, Slovin SF, Danila DC, Morris MJ, et al. A phase I trial of IGF-1R inhibitor cixutumumab and mTOR inhibitor temsirolimus in metastatic castration-resistant prostate cancer. Clin Genitourin Cancer. 2020;18:171–8.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Barata PC, Cooney M, Mendiratta P, Gupta R, Dreicer R, Garcia JA. Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer. Invest N Drugs. 2019;37:331–7.

    Article  CAS  Google Scholar 

  78. Meulenbeld HJ, De Bono JS, Tagawa ST, Whang YE, Li X, Heath KH, et al. Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC). Cancer Chemother Pharm. 2013;72:909–16.

    Article  CAS  Google Scholar 

  79. Amato RJ, Wilding G, Bubley G, Loewy J, Haluska F, Gross ME. Safety and preliminary efficacy analysis of the mTOR inhibitor ridaforolimus in patients with taxane-treated, castration-resistant prostate cancer. Clin Genitourin Cancer. 2012;10:232–8.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Al-Qatati A, Aliwaini S. Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells. Oncol Lett. 2017;14:7993–9.

    PubMed  PubMed Central  Google Scholar 

  81. Jo JH, Park HS, Lee DH, Han JH, Heo KS, Myung CS. Rosuvastatin inhibits the apoptosis of platelet-derived growth factor-stimulated vascular smooth muscle cells by inhibiting p38 via autophagy. J Pharm Exp Ther. 2021;378:10–19.

    Article  CAS  Google Scholar 

  82. Gorabi AM, Kiaie N, Aslani S, Sathyapalan T, Jamialahmadi T, Sahebkar A. Implications on the therapeutic potential of statins via modulation of autophagy. Longev OMAC. 2021;2021:9599608.

    Google Scholar 

  83. Toepfer N, Childress C, Parikh A, Rukstalis D, Yang W. Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription. Cancer Biol Ther. 2011;12:691–9.

    Article  CAS  PubMed  Google Scholar 

  84. He Z, Yuan J, Qi P, Zhang L, Wang Z. Atorvastatin induces autophagic cell death in prostate cancer cells in vitro. Mol Med Rep. 2015;11:4403–8.

    Article  CAS  PubMed  Google Scholar 

  85. Peltomaa AI, Raittinen P, Talala K, Taari K, Tammela TLJ, Auvinen A, et al. Prostate cancer prognosis after initiation of androgen deprivation therapy among statins users. A population-based cohort study. Prostate Cancer Prostatic Dis. 2021;24:917–924.98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Longo J, Freedland SJ, Penn LZ, Hamilton RJ. Statins and prostate cancer-hype or hope? The biological perspective. Prostate Cancer Prostatic Dis. 2022;25:650–6.

    Article  CAS  PubMed  Google Scholar 

  87. Alfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nat Rev Urol. 2017;14:107–19.

    Article  CAS  PubMed  Google Scholar 

  88. Ishola IO, Tijani HK, Dosumu OO, Anunobi CC, Oshodi TO. Atorvastatin attenuates testosterone-induced benign prostatic hyperplasia in rats: role of peroxisome proliferator-activated receptor-gamma and cyclo-oxygenase-2. Fundam Clin Pharm. 2017;31:652–62.

    Article  CAS  Google Scholar 

  89. Allott EH, Csizmadi I, Howard LE, Muller RL, Moreira DM, Andriole GL, et al. Statin use and longitudinal changes in prostate volume; results from the Reduction by Dutasteride of prostate Cancer Events (REDUCE) trial. BJU Int. 2020;125:226–33.

    Article  PubMed  Google Scholar 

  90. Hurwitz LM, Kulac I, Gumuskaya B, Valle JABD, Benedetti I, Pan F, et al. Use of aspirin and statins in relation to inflammation in benign prostate tissue in the placebo arm of the prostate cancer prevention trial. Cancer Prev Res (Philos). 2020;13:853–62.

    Article  Google Scholar 

  91. Zhang X, Zeng X, Dong L, Zhao X, Qu X. The effects of statins on benign prostatic hyperplasia in elderly patients with metabolic syndrome. World J Urol. 2015;33:2071–7.

    Article  CAS  PubMed  Google Scholar 

  92. Shih HJ, Huang CJ, Lin JA, Kao MC, Fan YC, Tsai PS. Hyperlipidemia is associated with an increased risk of clinical benign prostatic hyperplasia. Prostate. 2018;78:113–20.

    Article  CAS  PubMed  Google Scholar 

  93. Mills IW, Crossland A, Patel A, Ramonas H. Atorvastatin treatment for men with lower urinary tract symptoms and benign prostatic enlargement. Eur Urol. 2007;52:503–9.

    Article  CAS  PubMed  Google Scholar 

  94. Stamatiou KN, Zaglavira P, Skolarikos A, Sofras F. The effects of lovastatin on conventional medical treatment of lower urinary tract symptoms with finasteride. Int Braz J Urol. 2008;34:555–61.

    Article  PubMed  Google Scholar 

  95. Tiwari R, Fleshner N. The role of metformin, statins and diet in men on active surveillance for prostate cancer. World J Urol. 2022;40:61–69.

    Article  CAS  PubMed  Google Scholar 

  96. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care. 2021;44:111–24.

    Article  Google Scholar 

  97. Zaidi S, Gandhi J, Joshi G, Smith NL, Khan AS. The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis. 2023;22:351–61.

    Article  Google Scholar 

  98. Chen C, Wang H, Geng X, Zhang D, Zhu Z, Zhang G, et al. Metformin exerts anti-AR-negative prostate cancer activity via AMPK/autophagy signaling pathway. Cancer Cell Int. 2021;21:404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Nguyen HG, Yang JC, Kung HJ, Shi XB, Tilki D, Lara PN Jr, et al. Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. Oncogene. 2014;33:4521–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Joshua AM, Zannella VE, Downes MR, Hersey K, Koritzinsky M, Schwab M, et al. A pilot “window of opportunity” neoadjuvant study of metformin in localized prostate cancer. Prostate Cancer Prostatic Dis. 2014;17:252–8.

    Article  CAS  PubMed  Google Scholar 

  101. Kuo YJ, Sung FC, Hsieh PF, Chang HP, Wu KL, Wu HC. Metformin reduces prostate cancer risk among men with benign prostatic hyperplasia: A nationwide population-based cohort study. Cancer Med. 2019;8:2514–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pennanen P, Syvälä H, Bläuer M, Savinainen K, Ylikomi T, Tammela TLJ, et al. The effects of metformin and simvastatin on the growth of LNCaP and RWPE-1 prostate epithelial cell lines. Eur J Pharm. 2016;788:160–7.

    Article  CAS  Google Scholar 

  103. Zhu W, Xu H, Ma J, Guo J, Xue W, Gu B, et al. An open-label pilot study of metformin as a concomitant therapy on patients with prostate cancer undergoing androgen deprivation treatment. Urol Int. 2017;98:79–84.

    Article  CAS  PubMed  Google Scholar 

  104. Hong Y, Lee S, Won S. The preventive effect of metformin on progression of benign prostate hyperplasia: a nationwide population-based cohort study in Korea. PloS ONE. 2019;14:e0219394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li SX, Li C, Pang XR, Zhang J, Yu GC, Yeo AJ, et al. Metformin attenuates silica-induced pulmonary fibrosis by activating autophagy via the AMPK-mTOR signaling pathway. Front Pharm. 2021;12:719589.

    Article  CAS  Google Scholar 

  106. Eule CJ, Flaig TW, Wong K, Graf R, Lam ET. Effectiveness and durability of benefit of mTOR inhibitors in a real-world cohort of patients with metastatic prostate cancer and PI3K pathway alterations. Prostate Cancer Prostatic Dis. 2022;26:188–93.

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by the São Paulo Research Foundation—FAPESP under Grant number 2019/09912-9 and 2023/05123-5.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Guilherme Lemos, Cícera Madri Alves de Souza Fernandes & Fabiano Beraldi Calmasini

  2. Laboratory of Multidisciplinary Research, Sao Francisco University (USF), Bragança Paulista, SP, Brazil

    Fábio Henrique Silva

Authors
  1. Guilherme Lemos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cícera Madri Alves de Souza Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fábio Henrique Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fabiano Beraldi Calmasini
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GL and CMASF contributed to the writing of the manuscript, FHS and FBC participated in research design and wrote the manuscript and FBC revised the final version of the manuscript and was responsible for the final approval.

Corresponding author

Correspondence to Fabiano Beraldi Calmasini.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lemos, G., Fernandes, C.M.A.d.S., Silva, F.H. et al. The role of autophagy in prostate cancer and prostatic diseases: a new therapeutic strategy. Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00793-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41391-024-00793-4

Search

Advanced search

Quick links