Key players of neuroendocrine differentiation in prostate cancer
Editorial Commentary

Key players of neuroendocrine differentiation in prostate cancer

Matteo Santoni1#, Gaetano Aurilio2#, Alessandro Maccioni3, Franco Nolè2, Nicola Battelli1

1Oncology Unit, Macerata Hospital, Macerata, Italy; 2Medical Oncology Division of Urogenital and Head and Neck Tumours, IEO, European Institute of Oncology IRCCS, Milan, Italy; 3Direzione Area Vasta 3-ASUR, Marche, Italy

#These authors contributed equally to this work.

Correspondence to: Matteo Santoni, MD. Oncology Unit, Macerata Hospital, via Santa Lucia 2, 62100 Macerata, Italy. Email:

Provenance: This is an invited article commissioned by Section Editor Xiao Li (Department of Urology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China).

Comment on: Reina-Campos M, Linares JF, Duran A, et al. Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer. Cancer Cell 2019;35:385-400.e9.

Submitted May 06, 2019. Accepted for publication May 09, 2019.

doi: 10.21037/atm.2019.05.18

We read with interest the article entitled “Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer” recently published by Reina-Campos et al. on Cancer Cell (1), in which a pathogenetic hypothesis focusing on the protein kinase C (PKC)λ/ι loss that would favor the acquisition of neuroendocrine (NE) differentiation in prostate cancer (PC) models has been investigated.

Molecularly-based personalized interventions represent the “Holy Grail” for cancer researchers worldwide. Although several steps forward have been made on the route to precision medicine in PC (2-5), a complete comprehension of the processes of carcinogenesis, tumor progression and acquired drug resistance is still so far. These mechanisms include wide simultaneous genomic rearrangements that results into double-strand DNA breaks (“chromoplexy”) (6), de novo monoclonal seeding of daughter metastases (7), metabolic alterations in tumor cells (8,9) and the transdifferentiation to a NE-like phenotype characterized by tumor cell proliferation and invasion (10). On this background, NE features seem to play a significative role. NE differentiation can vary within a single patient along the natural history of PC and results highly prevalent in men treated with prolonged androgen-deprivation therapy (ADT), in which represents a mechanism for hormonal escape or androgen receptor (AR) independence (11,12).

The process of acquisition of NE differentiation has been poorly molecularly characterized due to the lack of tumor specific therapies but requires a series of key players that includes inflammation and autophagy. Indeed, in PC microenvironment, Tumor-Associated Macrophages (TAMs) secrete Interleukin (IL)-6 and promote the NE differentiation of PC cells (13,14). On the other hand, autophagy is involved in PC progression and modulates the sensitivity of this tumor to chemotherapy (12,15).

Thus, targeting NE differentiation may be the key to modulate tumor aggressiveness and response to therapy. Among emerging targets, Prostate Specific Membrane Antigen (PSMA) is demonstrating to be an ideal candidate for the diagnosis and treatment of PC (16,17). PSMA is an androgen-regulated membrane bound glycoprotein and is variably expressed in NE prostate cancer (NEPC). PSMA can act as a target for antibody-drug conjugated (ADC) therapies. At this regard, Petrylak et al. investigated the efficacy and safety of PSMA-ADC at 2.5 mg/kg in patients with taxane-refractory metastatic castration-resistant PC. Prostate-specific antigen (PSA) decline of ≥30% was observed in 36% of enrolled patients while Circulating Tumor Cell (CTC) decline of ≥50% was noticed in more than 70%, with an acceptable toxicity profile (11), thus supporting the development of further studies in this field.

On this scenario, the results published by Reina-Campos et al. (1) focused on PKCλ/ι loss open the way to a novel promising therapeutic strategy. The authors primarily demonstrated that in PC datasets the gene expression of PRKCI (coding for PKCλ/ι) was downregulated in metastases and correlated with a negative prognosis. Hence, both in primary and metastatic samples, PKCλ/ι downregulation appeared to be associated with NEPC phenotype, and also in a cohort of de novo hormone-naive NEPC samples lower PKCλ/ι levels were displayed. Likewise, in enzalutamide-resistant PC cell lines with related NE differentiation, PKCλ/ι was reduced as well. Of interest, in PC mouse lines the authors observed that the concomitant deletion of PTEN and PKCλ/ι drove to aggressive disease development and gain of NE features. On the same line, in two androgen-resistant cell lines, knock down of PKCλ/ι elicited NE markers in in vitro cells and in vivo tumor xenografts. In in vitro kinase assay, PKCλ/ι was able to inhibit mTORC1 activation through directed LAMTOR2 phosphorylation, the latter identified as a likely link among PKCλ/ι and mTORC1. The authors observed that in C42B cell lines with inactivation of PKCλ/ι (sgPKCλ/ι), mTORC1 turned out to be activated as displayed by western blot of three downstream effectors (p4EBP1, pS6K, and cMYC), and to play a crucial role toward NEPC differentiation. Along this line, through gene expression analysis on the same cellular model PKCλ/ι-deficient, ATF4 resulted as the main upstream regulator of the transcriptional changes, and its increase was confirmed by western blot analysis. In sgPKCλ/ι cells, knock down of ATF4 was associated with decreased NEPC levels and slowed cell proliferation. Furthermore, gene set enrichment analysis pointed out meaningful enrichment in sgPKCλ/ι cells of a metabolic serine, glycine, one-carbon pathway (SGOCP), which is of paramount importance for sustaining cell proliferation and epigenetic changes through S-adenosyl methionine (SAM) production. The mTORC1/ATF4 axis definitely induced a metabolic cell reprogramming to enhance the flux of methyl donors SGOCP-stimulated finally fostering NE differentiation. Again, in a comparison among human samples of adenocarcinoma and NEPC both with mTORC1 iperexpression, higher PHGDH levels were detected in de novo NEPC tissues and in NEPC lesions developing after therapy, so underlining also the role of PHGDH in the mTORC1/ATF4 axis. Of clinical relevance, the authors observed that DNA methylated regions in sgPKCλ/ι cells exhibited a significant overlapping with hypermethylated areas in NEPC tumors and in lethal PC subtypes as well. Lastly, the authors explored a therapeutic target involving SGOCP and DNA methylation. In detail, sgPKCλ/ι cells treated with decitabine inhibitor of DNA methyltrasferase activity or with cycloleucine inhibitor of SAM production proved a strong reduction of NEPC markers along with a remarkable anti-proliferative effect.

In conclusion, the study led by Reina-Campos et al. showed that targeting PKCλ/ι may be feasible in order to modulate the NE differentiation of PC cells and, as a consequence, to reduce tumor aggressiveness and drug resistance. The possibility to sequence or combine PKCλ/ι-targeted approaches with current and future hormonal therapies and chemotherapies should be further investigated in randomized clinical trials.




Conflicts of Interest: The authors have no conflicts of interest to declare.


  1. Reina-Campos M, Linares JF, Duran A, et al. Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer. Cancer Cell 2019;35:385-400.e9. [Crossref] [PubMed]
  2. Montironi R, Santoni M, Lopez-Beltran A, et al. Morphologic and molecular backgrounds for personalized management of genito-urinary cancers: an overview. Curr Drug Targets 2015;16:96-102. [Crossref] [PubMed]
  3. Santoni M, Scarpelli M, Mazzucchelli R, et al. Current Histopathologic and Molecular Characterizations of Prostate cancer: Towards Individualized Prognosis and Therapies. Eur Urol 2016;69:186-90. [Crossref] [PubMed]
  4. Ciccarese C, Santoni M, Massari F, et al. Present and future of personalized medicine in adult genitourinary tumors. Future Oncol 2015;11:1381-8. [Crossref] [PubMed]
  5. Ciccarese C, Santoni M, Brunelli M, et al. AR-V7 and prostate cancer: The watershed for treatment selection? Cancer Treat Rev 2016;43:27-35. [Crossref] [PubMed]
  6. Baca SC, Prandi D, Lawrence MS, et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153:666-77. [Crossref] [PubMed]
  7. Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015;520:353-7. [Crossref] [PubMed]
  8. Ciccarese C, Santoni M, Massari F, et al. Metabolic alterations in Renal and Prostate cancer. Curr Drug Metab 2016;17:150-5. [Crossref] [PubMed]
  9. Swinnen JV, Vanderhoydonc F, Elgamal AA, et al. Selective activation of the fatty acid synthesis pathway in human prostate cancer. Int J Cancer 2000;88:176-9. [Crossref] [PubMed]
  10. Santoni M, Conti A, Burattini L, et al. Neuroendocrine differentiation in prostate cancer: novel morphological insights and future therapeutic perspectives. Biochim Biophys Acta 2014;1846:630-7. [PubMed]
  11. Petrylak DP, Smith DC, Appleman LJ, et al. A phase 2 trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2014;32:abstr 5023.
  12. Mollica V, Di Nunno V, Cimadamore A, et al. Molecular Mechanisms Related to Hormone Inhibition Resistance in Prostate Cancer. Cells 2019. [Crossref] [PubMed]
  13. Lee GT, Kwon SJ, Lee JH, et al. Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. Prostate 2011;71:1525-37. [PubMed]
  14. Santoni M, Cheng L, Conti A, et al. Activity and functions of tumor-associated macrophages in prostate carcinogenesis. Eur Urol Suppl 2017;16:301-8. [Crossref]
  15. Chang PC, Wang TY, Chang YT, et al. Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. PLoS One 2014;9:e88556. [Crossref] [PubMed]
  16. Santoni M, Scarpelli M, Mazzucchelli R, et al. Targeting prostate-specific membrane antigen for personalized therapies in prostate cancer: morphologic and molecular backgrounds, and future promises. J Biol Regul Homeost Agents 2014;28:555-63. [PubMed]
  17. Cimadamore A, Cheng M, Santoni M, et al. New Prostate Cancer Targets for Diagnosis, Imaging, and Therapy: Focus on Prostate-Specific Membrane Antigen. Front Oncol 2018;8:653. [Crossref] [PubMed]
Cite this article as: Santoni M, Aurilio G, Maccioni A, Nolè F, Battelli N. Key players of neuroendocrine differentiation in prostate cancer. Ann Transl Med 2019;7(Suppl 3):S112. doi: 10.21037/atm.2019.05.18