bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–06–15
seven papers selected by
Grigor Varuzhanyan, UCLA
  1. OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer.
  2. KAT5 promotes tumor growth in androgen-independent prostate cancer by facilitating aerobic glycolysis.
  3. Loss of UFMylation supports prostate cancer metastasis and rewires cell metabolism towards hexosamine biosynthesis.
  4. Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer.
  5. Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.
  6. Lack of synergy between AR targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer.
  7. Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer.
  1. bioRxiv. 2025 Jun 01. pii: 2025.05.28.656673. [Epub ahead of print]
    OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer.
    Matthew J Bernard, Angel Ruiz, Johnny A Diaz, Nicholas M Nunley, Rachel N Dove, Kylie Y Heering, Sachi Bopardikar, Andrea Gallardo, Takao Hashimoto, Raag Agrawal, Chad M Smith, Blake R Wilde, Nedas Matulionis, Helen M Richards, Marina N Sharifi, Joshua M Lang, Shuang G Zhao, Michael C Haffner, Paul C Boutros, Heather R Christofk, Andrew S Goldstein.
      Cells regularly adapt their metabolism in response to changes in their microenvironment or biosynthetic needs. Prostate cancer cells leverage this metabolic plasticity to evade therapies targeting the androgen receptor (AR) signaling pathway. For example, nucleotide metabolism plays a critical role in treatment-resistant prostate cancer by supporting DNA replication, DNA damage response and cell fate decisions. Identifying novel regulators of nucleotide metabolism in treatment-resistant cancer that are dispensable for the health of normal cells may lead to new therapeutic approaches less toxic than commonly used chemotherapies targeting nucleotide metabolism. We identify the metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as a regulator of nucleotide metabolism, tumor growth, and treatment-induced plasticity in prostate cancer. While OGDHL is a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation while having minimal impact on TCA cycle activity. Loss of OGDHL profoundly decreases nucleotide metabolite pools, induces the DNA damage response marker Ɣ2AX, and alters androgen receptor inhibition-induced plasticity, including suppressing the neuroendocrine markers DLL3 and HES6. Finally, OGDHL is highly expressed in neuroendocrine prostate cancer (NEPC). These findings support an unexpected role of OGDHL in prostate cancer, where it functions to sustain nucleotide pools for proliferation, DNA repair, and AR inhibition-induced plasticity.
    DOI:  https://doi.org/10.1101/2025.05.28.656673
  2. Transl Oncol. 2025 Jun 07. pii: S1936-5233(25)00167-6. [Epub ahead of print]58 102436
    KAT5 promotes tumor growth in androgen-independent prostate cancer by facilitating aerobic glycolysis.
    Wei He, Juping Zhao, Jun Dai, Chen Fang, Xin Huang, Chenghe Wang, Yi Gao, Fukang Sun, Xin Xie.
      This study aimed to explore the exact roles of lysine acetyltransferase 5 (KAT5) in prostate cancer (PCa). PCa tumour tissue samples and paired adjacent normal prostate tissues as well as three PCa cell lines were used. Gene expression was determined utilizing real-time PCR, western blotting and immunohistochemical staining. Cell viability, migration, and invasion was determined utilizing CCK-8, Transwell and Scratch assays, respectively. Levels of glucose, lactate, and ATP were measured utilizing corresponding assay kits. Extracellular acidification rate (ECAR) and oxygen consumption rates (OCR) were measured using Seahorse method. Xenografted tumor mice model was established to detect the roles of KAT5 in vivo. KAT5 expression was elevated in PCa tissue and cell lines, particularly in castration-resistant PCa tissue and DU145 cells. Overexpression of KAT5 promoted proliferation, migration, invasion, and expression of phosphorylated p38 and JNK of DU145 cells, whereas such effects was reversed after transfecting si-KAT5 or inhibiting p38 and JNK. KAT5 expression positively correlated with PKM and GLUT1, and its overexpression elevated PKM2 and GLUT1 levels. KAT5 overexpression promoted glucose uptake, lactate production, ATP levels in DU145 cells, and these were reversed after si-KAT5 treatment or inhibiting p38 and JNK. ECAR and OCR assays further confirmed that KAT5 facilitating aerobic glycolysis. After inhibiting glycolysis using 2-DG, KAT5 mediated cells proliferation was partly suppressed. Inhibition KAT5 expression suppressed tumor growth in vivo. KAT5 may involve in PCa tumor progression via p38-mediated aerobic glycolysis, which might be a promising anti-tumor strategy in PCa.
    Keywords:  Aerobic glycolysis; Castration-resistant prostate cancer; KAT5; PKM2; Prostate cancer
    DOI:  https://doi.org/10.1016/j.tranon.2025.102436
  3. bioRxiv. 2025 Jun 04. pii: 2025.06.02.657324. [Epub ahead of print]
    Loss of UFMylation supports prostate cancer metastasis and rewires cell metabolism towards hexosamine biosynthesis.
    Laura Bozal-Basterra, María-Camila Salazar, Ana Margarida Ferreira Campos, Margherita Demicco, Daniel R Schmidt, Klaudia Sobczak, June Ereño-Orbea, Patricia Altea-Manzano, Ainara Miranda Villanueva, Belén Martínez La Osa, Saioa Garcia-Longarte, María Ponce-Rodriguez, Isabel Mendizabal, Onintza Carlevaris, Ianire Astobiza, Natalia Martin-Martin, Amaia Zabala-Letona, Ana Talamillo, Juan Fernández-García, Mikel Azkargorta, Ibon Iloro, Rosa Barrio, Félix Elortza, Sarah-Maria Fendt, Matthew G Vander Heiden, Jesús-Jiménez Barbero, James D Sutherland, Arkaitz Carracedo.
      The acquisition of metastatic features in tumor cells encompasses genetic and non-genetic adaptation, including reprogramming of cellular metabolism. Here we show that loss of UFMylation reroutes glucose metabolism, promotes invasive capacity and supports prostate cancer metastasis. Through transcriptome-based bioinformatics analysis, we identified a reduction in the ubiquitin-like modifier UFM1 and its ligase UFL1 in metastatic prostate cancer. We demonstrate that loss of UFMylation results in enhanced cancer cell dissemination and a switch from cellular proliferation to invasion. Using biotin-based proteomics, we identified phosphofructokinase (PFKAP) as an unprecedented UFMylation substrate. Consistent with UFMylation playing a role in the regulation of phosphofructokinase activity, loss of UFMylation reduced glucose metabolism in favour of hexosamine biosynthesis, which resulted in elevated glycosylation of proteins relevant for cell invasion. These results reveal a role for UFMylation in the regulation of phosphofructokinase and glucose metabolism to support prostate cancer metastasis.
    DOI:  https://doi.org/10.1101/2025.06.02.657324
  4. Cell Rep. 2025 Jun 06. pii: S2211-1247(25)00563-7. [Epub ahead of print]44(6): 115792
    Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer.
    Chenchu Lin, Thomas L Pulliam, Jenny J Han, Jiaqian Xu, Carlos Vera Recio, Sandi R Wilkenfeld, Yan Shi, Manoj Kushwaha, Sarah Bench, Eduardo Ruiz, Sanjanaa Senthilkumar, Jayasurya Dileep, Peter D A Shepherd, Nora M Navone, Albert R Klekers, Elizabeth M Whitley, Michael M Ittmann, Livia S Eberlin, Wenyi Wang, Daniel E Frigo.
      Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family members CREB1 and ATF1 exhibit close redundancy, necessitating co-targeting for optimal anti-tumor efficacy. An inhibitor of CREB1/ATF1 blocks CRPC with minimal side effects. Mechanistically, CAMKK2 and CREB increase CRPC growth through augmenting cholesterol metabolism. Together, these findings identify an oncogenic pathway that could be exploited for the treatment of CRPC.
    Keywords:  AMPK; CAMKI; CAMKK2; CP: Cancer; CP: Metabolism; CREB; androgen receptor; cholesterol; metabolism; prostate cancer
    DOI:  https://doi.org/10.1016/j.celrep.2025.115792
  5. PLoS One. 2025 ;20(6): e0325509
    Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.
    Floriana Jessica Di Paola, Luiza Hd Cardoso, Efterpi Nikitopoulou, Bianca Kulik, Sandra Rühl, Alexander Eva, Natascha Sommer, Thomas Linn, Erich Gnaiger, Klaus Failing, Kathrin Büttner, Christian Frezza, Sybille Mazurek.
      Mitochondrial glycerol 3-P dehydrogenase (mtG3PDH) plays a significant role in cellular bioenergetics by serving as a rate-limiting element in the glycerophosphate shuttle, which connects cytosolic glycolysis to mitochondrial oxidative metabolism. mtG3PDH was identified as an important site of electron leakage leading to ROS production to the mitochondrial matrix and intermembrane space. Our research focused on the role of two published mtG3PDH inhibitors (RH02211 and iGP-1) on the proliferation and metabolism of PC-3 and DU145 prostate cancer cells characterized by different mtG3PDH activities. Since pyruvate as a substrate of lactate dehydrogenase (LDH) may represent an escape mechanism for the recycling of cytosolic NAD+ via the glycerophosphate shuttle, we investigated the effect of pyruvate on the mode of action of the mtG3PDH inhibitors. Extracellular pyruvate weakened the growth-inhibitory effects of RH02211 and iGP-1 in PC-3 cells but not in DU145 cells, which correlated with higher H-type LDH and lower mitochondrial glutamate-oxaloacetate transaminase in DU145 cells. In the pyruvate-low medium, the strength of inhibition was more pronounced in PC-3 cells, characterized by higher mtG3PDH activities compared to DU145 cells. Pyruvate conversion rates (production in pyruvate-low and consumption in pyruvate-high PC-3 cells) were not impaired by RH02211 and iGP-1, suggesting that the conversion of extracellular pyruvate to lactate was not the primary factor responsible for the weakening effect of extracellular pyruvate on the RH02211-induced inhibition of PC-3 proliferation. In pyruvate-high PC-3 cells, the intracellular glycerol-3-P and dihydroxyacetone-P concentrations were consistent with an inhibition of mtG3PDH. In contrast, in pyruvate-low cells, the concentrations of these metabolites suggested an activation of mtG3PDH in parallel with an impairment of cytosolic G3PDH by RH02211. Of all metabolic characterizations recorded in this study (fluxes, intracellular intermediates, O2 consumption and H2O2 production), the decrease in glutaminolysis correlated best with the RH02211-induced inhibition of proliferation in pyruvate-low and pyruvate-high PC-3 cells.
    DOI:  https://doi.org/10.1371/journal.pone.0325509
  6. bioRxiv. 2025 Jun 03. pii: 2025.06.02.657429. [Epub ahead of print]
    Lack of synergy between AR targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer.
    Nicole A Traphagen, Esmé Wheeler, Rong Li, Feng Lu, Buraq Ahmed, Alok K Tewari, Steven P Balk, Peter S Nelson, Eva Corey, Henry Long, Alan D D'Andrea, Xintao Qiu, Myles Brown.
      Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous-recombination proficient prostate cancer.
    STATEMENT OF SIGNIFICANCE: Androgen deprivation does not inhibit DNA repair and does not synergize with PARP inhibition in prostate cancer with intact homologous recombination repair.
    DOI:  https://doi.org/10.1101/2025.06.02.657429
  7. Acta Pharm Sin B. 2025 Apr;15(4): 2095-2113
    Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer.
    Dan Feng, Jian Zhang, Huanmin Niu, Xiaoxue Zheng, Mengqi Jia, Qiqi Lu, Jing Wang, Wenxue Guo, Qi Sun, Huiqing Yuan, Hongxiang Lou.
      The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe2+ levels in vitro. Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe2+, is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.
    Keywords:  EIF5A; Ferroptosis; HMOX1; NRF2; Polyamines; Prostate cancer; Proteasome; Spermidine
    DOI:  https://doi.org/10.1016/j.apsb.2025.02.023
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