Chemotherapy Resistance In Prostate Cancer Research Articles

Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer.

Prostate cancer (PCa) ranks as the sixth most serious male malignant disease globally. While docetaxel (DTX) chemotherapy is the standard treatment for advanced PCa patients with distant metastasis, some individuals exhibit insensitivity or resistance to DTX. Cancer-associated fibroblasts (CAFs) play a pivotal role as stromal cells within the tumor microenvironment, influencing tumor development, progression, and drug resistance through exosomes. Ferroptosis, a novel form of programmed cell death, is characterized by intracellular iron accumulation that triggers lipid peroxidation, ultimately leading to cell demise. To delve into the potential mechanisms of chemotherapy resistance in prostate cancer, our research delved into the impact of CAF-derived exosomes on ferroptosis. Our findings revealed that CAF exosomes hindered the buildup of lipid reactive oxygen species (ROS) in prostate cancer cells induced by erastin, as well as mitigated erastin-induced mitochondrial damage, thereby impeding iron-induced cell death in prostate cancer cells. Furthermore, miR-432-5p was identified to diminish glutathione (GSH) consumption by targeting CHAC1, consequently inhibiting ferroptosis in prostate cancer cells. Our study found that miR-432-5p, originating from cancer-associated fibroblast (CAF) exosomes, suppresses ferroptosis by targeting CHAC1, thereby increasing resistance to docetaxel (DTX) in PCa. This research introduces a novel approach to address resistance to DTX.

Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer

R-loops are prevalent three-stranded nucleic acid structures, comprising a DNA-RNA hybrid and a displaced single-stranded DNA, that frequently form during transcription and may be attributed to genomic stability and gene expression regulation. It was recently discovered that RNA modification contributes to maintain the stability of R-loops such as N6-methyladenosine (m6A). Yet, m6A-modified R-loops in regulating gene transcription remains poorly understood. Here, we demonstrated that insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) recognize R-loops in an m6A-dependent way. Consequently, IGF2BPs overexpression leads to increased overall R-loop levels, cell migration inhibition, and cell growth retardation in prostate cancer (PCa) via precluding the binding of DNA methyltransferase 1(DNMT1) to semaphorin 3 F (SEMA3F) promoters. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A-containing R-loops and are required for tumor suppressor functions. Overexpression of SEMA3F markedly enhanced docetaxel chemosensitivity in prostate cancer via regulating Hippo pathway. Our findings point to a distinct R-loop resolution pathway mediated by IGF2BPs, emphasizing the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology.The manuscript summarizes the new role of N6-methyladenosine in epigenetic regulation, we introduce the distinct R-loop resolution mediated by IGF2BP proteins in an m6A-dependent way, which probably lead to the growth retardation and docetaxel chemotherapy resistance in prostate cancer. Moreover, our findings first emphasized the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology. In addition, our research provides a novel RBM15/IGF2BPs/DNMT1 trans-omics regulation m6A axis, indicating the new crosstalk between RNA m6A methylation and DNA methylation in prostate cancer.Graphical

Inhibition of Ribonucleotide Reductase Induces Endoplasmic Reticulum Stress and Apoptosis, Leading to the Death of Docetaxel-resistant Prostate Cancer Cells.

The development of chemotherapy resistance in prostate cancer (PCa) patients poses a significant obstacle to disease progression. Ribonucleotide reductase is a crucial enzyme for cell division and tumor growth. Triapine, an inhibitor of ribonucleotide reductase, has shown strong anti-tumor activity in various types of cancers. However, the effect of triapine on docetaxel-resistant (DR) human PCa cells has not been explored previously. This study aimed to examine the potential anti-proliferative effects of triapine in PC3-DR (docetaxel-resistant) cells. Cell viability was determined by the MTT test, and apoptosis and cell cycle progression were analyzed by image-based cytometer. mRNA and protein expression were assessed by RT-qPCR and western blot, respectively. Triapine administration significantly reduced PC3 and PC3-DR cells' survival, while the cytotoxic effect was higher in PC3-DR cells. Cell death resulting from inhibition of ribonucleotide reductase was mediated by endoplasmic reticulum stress, induction of apoptosis, and cell cycle arrest. The findings were supported by the upregulation of caspases, Bax, Bak, P21, P27, P53, TNF-α, FAS, and FASL, and downregulation of Bcl2, Bcl-XL, cyclin-dependent kinase 2 (CDK2), CDK4, cyclins, and heat shock proteins expression. According to the data, the reduction of ABC transporter proteins and NF-ĸB expression may play a role in triapine-mediated cytotoxicity in docetaxel-resistant cells. Based on our findings, triapine emerges as a promising chemotherapeutic approach for combating docetaxel- resistant prostate cancer.

Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer.

Acquired treatment resistance is an important cause of death in prostate cancer, and this study aimed to explore the mechanisms of chemotherapy resistance in prostate cancer. We employed castration-resistant prostate cancer (CRPC), neuroendocrine prostate cancer (NEPC), and chemotherapy-resistant prostate cancer datasets to screen for potential target genes. The Cancer Genome Atlas (TCGA) was used to detect the correlation between the target genes and prognosis and clinical characteristics. Nei endonuclease VIII-like 3 (NEIL3) knockdown cell lines were constructed with RNA interference. Prostate cancer cells were treated with enzalutamide for the androgen deprivation therapy (ADT) model, and with docetaxel and cisplatin for the chemotherapy model. Apoptosis and the cell cycle were examined using flow cytometry. RNA sequencing and western blotting were performed in the knockdown Duke University 145 (DU145) cell line to explore the possible mechanisms. The TCGA dataset demonstrated that high NEIL3 was associated with a high T stage and Gleason score, and indicated a possibility of lymph node metastasis, but a good prognosis. The cell therapy models showed that the loss of NEIL3 could promote the chemotherapy resistance (but not ADT resistance) of prostate cancer (PCa). Flow cytometry revealed that the loss of NEIL3 in PCa could inhibit cell apoptosis and cell cycle arrest under cisplatin treatment. RNA sequencing showed that the knockdown of NEIL3 changes the expression of neuroendocrine-related genes. Further western blotting revealed that the loss of NEIL3 could significantly promote the phosphorylation of ATR serine/threonine kinase (ATR) and ATM serine/threonine kinase (ATM) under chemotherapy, thus initiating downstream pathways related to DNA repair. In summary, the loss of NEIL3 promotes chemotherapy resistance in prostate cancer, and NEIL3 may serve as a diagnostic marker for chemotherapy-resistant patients.

SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.

Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-\u03b2 signaling pathway

Therapeutic failure in prostate cancer (PC) is believed to result from its unusually invasive and metastatic nature. Cancer-associated fibroblasts (CAFs) are essential in the tumor microenvironment. We intended to study the role of CAF-derived exosomes in the context of PC and the potential regulatory mechanism associated with miR-423-5p and GREM2. CAF-derived exosomes decreased the chemosensitivity of parental PC cells and enhanced the drug resistance of drug-resistant cells. PC-associated fibroblast-derived exosomes carrying miR-423-5p increased the resistance of PC to taxane by inhibiting GREM2 through the TGF-β pathway. Inhibition of the TGF-β pathway partially reversed the increased drug resistance in PC cells induced by CAF-derived exosomes. Inhibition of miR-423-5p enhanced the drug sensitivity of PC cells in vivo. We showed that CAF-secreted exosomal miR-423-5p promoted chemotherapy resistance in PC by targeting GREM2 through the TGF-β pathway. This study may allow the development of novel approaches for PC.

P36 - p300 up-regulation by docetaxel contributes to chemotherapy resistance in prostate cancer

P36 - p300 up-regulation by docetaxel contributes to chemotherapy resistance in prostate cancer

Abstract 2064: CHRM1-mediated acetylcholine signaling protects prostate cancer cells from the chemotherapy agent docetaxel

Abstract Background: Chemotherapy-resistant prostate cancer (PCa) remains a leading cause of cancer-related deaths in advanced PCa patients. The current study investigates the role of acetylcholine (ACh) signaling in the development and maintenance of chemotherapy resistance in PCa. Methods: Human PCa cell cultures were used to harvest total RNA and protein for qPCR and Western blot analyses, respectively. The chemotherapy drug docetaxel’s (DTX) ability to induce apoptosis was measured with crystal violet survival assays and Western blot analysis of pro-apoptotic proteins. Results: Treatment of the androgen-independent human PCa cell lines 22Rv1 and DU145 with a low concentration of DTX at 1 nM increases the expression of the key ACh production and secretion enzymes choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and the high-affinity choline transporter 1 (CHT1), which is accompanied by a 4-fold increase in ACh secretion. These genes also show increased expression in DTX-resistant 22Rv1 cells. The muscarinic receptor system further shows alterations in gene expression with low-concentration DTX treatment and acquired DTX resistance. Specifically, across all 5 muscarinic cholinergic receptors (CHRM1-5), the expression of CHRM1 is increased in both circumstances. Treatment of both DTX-sensitive and -resistant cell lines with a combination of DTX and the CHRM1 antagonist dicyclomine decreases cell survival, lowers DTX IC50 values (DU145: 62%; 22Rv1: 48%; DTX-resistant 22Rv1: 23%), and enhances the expression of the pro-apoptotic proteins cleaved caspase-3 and cleaved PARP1 compared to treatment with DTX alone. This is paralleled by the observations that treatment with the ACh mimetic carbachol (CCh) protects cells from DTX treatment. Mechanistically, ACh signaling protects PCa cells from DTX through activation of the extracellular signal-regulated kinase / cAMP response element binding protein 1 (ERK/CREB) pathway. Treatment of 22Rv1 cells with CCh increases levels of the active phosphorylated forms of both ERK1/2 and CREB within 30 min. This increase is inhibited by the pan muscarinic receptor antagonist atropine and is not affected by the pan nicotinic receptor antagonist tubocurarine. Treatment of 22Rv1 cells with a combination of DTX and either the ERK inhibitor UO-126 or the CREB inhibitor 666-15 decreases cell survival in a synergistic manner. Conclusion: DTX induces an enhancement of ACh signaling in PCa cells, which may contribute to the development and maintenance of DTX resistance through CHRM1 and the downstream ERK/CREB pathway. Antagonism of CHRM1 and its downstream effectors may be useful in preventing and reverting chemotherapy resistance in PCa. Citation Format: Tyler Bland, Karen Vo, Baron Bechtold, Boyang Wu. CHRM1-mediated acetylcholine signaling protects prostate cancer cells from the chemotherapy agent docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2064.

Correction: Infiltrating mast cells increase prostate cancer chemotherapy and radiotherapy resistances via modulation of p38/p53/p21 and ATM signals.

[This corrects the article DOI: 10.18632/oncotarget.6372.].

The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling.

Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer’s stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated Notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer’s stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.

24 - Identification of predictive serum biomarkers for chemotherapy resistance in prostate cancer using mass spectrometric proteome analysis

24 - Identification of predictive serum biomarkers for chemotherapy resistance in prostate cancer using mass spectrometric proteome analysis

Overcoming Chemotherapy Resistance in Prostate Cancer

Although treatment for prostate cancer has improved over the past several years, taxanes remain the only form of chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In addition to the promising therapeutic cancer vaccines and newly developed agents targeting androgen receptor signaling, chemotherapy-based treatments will likely continue to play a significant role in patients with mCRPC. Recently published data that showed that a second taxane (cabazitaxel) extends survival after progression on docetaxel was a significant step forward, but also highlighted the need to overcome taxane resistance in prostate cancer. Preliminary evidence suggests that several treatment strategies may improve the activity of taxanes in prostate cancer and perhaps enhance clinical outcomes.

Highlights of This Issue

Metformin is a widely-used antidiabetic drug whose anticancer effects represent a promising and novel approach for the treatment of cancer. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with the AMPK/mTOR pathway. Rocha and colleagues tested the combination of metformin and paclitaxel and showed that combined treatment is more effective at arresting cells in the G2/M phase of the cell cycle, decreasing tumor growth, and increasing apoptosis in tumor-bearing mice. These results demonstrate that different drugs may cooperate to increase anti-growth signals and suggest that activation of AMPK may be an alternative therapeutic strategy in cancer treatment.Important advances have been made recently in the treatment of prostate cancer, with several drugs for metastatic, castration-resistant prostate cancer obtaining FDA approval in 2010 and 2011. In this issue of CCR Focus, guest editors Gerhardt Attard and Johann de Bono discuss the recent progress that has been made in prostate cancer therapy. Topics covered include targeting continued androgen receptor signaling; immunotherapeutic approaches in prostate cancer; the use of circulating tumor cells as treatment response biomarkers; and overcoming chemotherapy resistance in prostate cancer. Particular emphasis is put on the impact of newly approved agents (abiraterone, sipuleucel-T, and cabazitaxel).Bone metastases are ultimately responsible for the death of 500,000 patients worldwide every year. Investigators have been unable to study the molecular events underlying bone metastasis in these patients because of the lack of quality tissue available for study. Here, Mehra and colleagues present the discovery of nonossified bone metastases from multiple patients with advanced prostate cancer and their subsequent characterization and comparison to nonosseous metastases from the same patients. This represents a versatile and practical approach that may be used to characterize the steps in metastasis and opens important new possibilities for clinical monitoring through biomarker evaluation during treatment.KIT is an important oncogene in mucosal melanoma. In this issue, Omholt and colleagues studied mucosal melanomas from several different anatomical sites and found a significantly higher frequency of KIT mutations in melanomas of the vulva compared with melanomas of other mucosal sites (35% versus 10%). Using immunohistochemistry, the authors also found that ERK and AKT were activated in a large proportion of mucosal melanoma samples. Targeting the KIT downstream RAF-MEK-ERK and PI3K-AKT signaling pathways may represent a promising alternative therapeutic approach in mucosal melanoma, especially in the subset of tumors lacking activating KIT mutations.

C225 enhanced cisplatin induced non-androgen depended prostate cancer cell line PC-3 supression

Objective To investigate if C225 is available to enhance the supression effection of cisplatin on non-androgen depended prostate cancer cell line PC-3. Methods The expression levels of epidermal growth factor receptor (EGFR) and pEGFR in PC-3 cells were examed after sigle cisplatin or combined C225 exposure. Methylthiazol tetrazolium (MTT) , Transwell invasion test, cell-cell adhension, flow cytometry (FCM) and electronmicroscope were used to study the distinctions between different treated groups. The supematant prostate specific antigen (PAS) levels was detected by enzyme linked immunosorbene assay (ELISA). Results After C225 exposure, pEGFR levels were deregulated (0. 88 ± 0. 11,1.19 ± 0. 21 vs 0. 52 ± 0. 17). And C225 combined cisplatin could inhibit cell proliferation, invasion (422. 3 ±22. 3,304. 3 ± 39. 6 vs 194. 1 ± 84. 8 ) and adhesion ability ( 60 min 1593. 8 ± 29. 3, 1433.5 ± 30. 1 vs 1120. 5 ±43.4;90 min 1387. 6 ± 33.1,1304. 9 ± 22.4 vs 1035. 7 ± 20. 5 ), arrest cells in G0/G1 phase [(54. 2 ± 5.2) %, (66. 7 ± 4. 4) % vs (79. 3 ± 2. 5 ) %], enhance cell apoptosis rate[early phase (7. 6 ±4.4)%,(8.3±5.0)% vs (17.3 ±2.5)% ;late phase (6. 1 ±2. 1)%,(14.6 ±4. 1)% vs (21.8 ±2. 0)%],and suppressed PSA levels (0. 0317 ±0. 0041,0. 0293 ±0. 0025 vs 0. 0108 ±0. 0011 ). Conclusion C225 could inhibit cisplatin induced EGFR activation, which possibly related to prostate cancer chemotherapy resistance. And pre-treated with C225 could be another novel cadidate pathway to enhance cisplatin supression on non-androgen depended prostate cancer. Key words: C225; Cisplatin; Prostate cancer; Chemothearpy