MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1).

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CYP11A1 inhibition as a therapeutic approach for the treatment of castration resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.340 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 340-340 ◽

Cited By ~ 2

Author(s):

Riikka Oksala ◽

Mari Karimaa ◽

Outi Simola ◽

Meri Ramela ◽

Reetta Riikonen ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Steroid Hormones ◽

Castration Resistant Prostate Cancer ◽

Plasma Acth ◽

Steroid Synthesis ◽

Androgen Synthesis ◽

Castration Resistant ◽

Toxicological Studies

340 Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC.

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Drug Repurposing of Pantoprazole and Vitamin C Targeting Tumor Microenvironment Conditions Improves Anticancer Effect in Metastatic Castration-Resistant Prostate Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.660320 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhoulei Li ◽

Peng He ◽

Yali Long ◽

Gang Yuan ◽

Wanqing Shen ◽

...

Keyword(s):

Prostate Cancer ◽

Vitamin C ◽

Tumor Growth ◽

Cancer Cells ◽

Cell Lines ◽

Combined Treatment ◽

Drug Repurposing ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

18F Fdg

The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC.

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KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.679173 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lin Gao ◽

Ru Zhao ◽

Junmei Liu ◽

Wenbo Zhang ◽

Feifei Sun ◽

...

Keyword(s):

Prostate Cancer ◽

Signaling Pathway ◽

Growth Factor Receptor ◽

Clinical Problem ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Castration Resistant Prostate Cancer ◽

Egfr Signaling ◽

Castration Resistant ◽

Egfr Signaling Pathway

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

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Enhanced inhibition of tumor growth using TRAIL-overexpressing adipose-derived stem cells in combination with the chemotherapeutic agent CPT-11 in castration-resistant prostate cancer

Prostate International ◽

10.1016/j.prnil.2020.07.002 ◽

2020 ◽

Author(s):

Jae Heon Kim ◽

Eunjung Oh ◽

Yong Seok Han ◽

Sang Hun Lee ◽

Yun Seob Song

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Tumor Growth ◽

Chemotherapeutic Agent ◽

Adipose Derived Stem Cells ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Inhibition Of Tumor Growth

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Carboxylesterase - TRAIL expressing human adipose stem cells inhibit tumor growth in castration resistant prostate cancer bearing mice with less toxicity

European Urology Supplements ◽

10.1016/s1569-9056(19)30971-6 ◽

2019 ◽

Vol 18 (1) ◽

pp. e1343

Author(s):

Y.S. Song ◽

E.J. Oh ◽

S.H. Lee ◽

E.S. Song ◽

J.H. Kim ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Tumor Growth ◽

Adipose Stem Cells ◽

Castration Resistant Prostate Cancer ◽

Inhibit Tumor Growth ◽

Castration Resistant ◽

Human Adipose Stem Cells

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The emerging role of noncoding RNA in prostate cancer progression and its implication on diagnosis and treatment

10.31234/osf.io/4u2sd ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Cancer Progression ◽

Noncoding Rna ◽

Castration Resistant Prostate Cancer ◽

Systematic Analysis ◽

Castration Resistant ◽

Insight Into ◽

Generation Sequencing

Recent transcriptome studies using next-generation sequencing have detected aberrant changes in the expression of noncodingRNAs (ncRNAs) associated with cancer. For prostate cancer, the expression levels of ncRNAs including microRNAsand long noncoding RNAs are strongly associated with diagnosis, carcinogenesis and tumor growth. Moreover, androgenand its cognate receptor, androgen receptor (AR), regulate various signaling pathways for prostate tumor growth. In addition,progression to lethal castration-resistant prostate cancer (CRPC) is also owing to AR function. Systematic analysis ofAR-binding sites and their regulated transcripts revealed that many ncRNAs are widely regulated at the transcriptionallevel. Thus, recent studies provide new insight into the complicated molecular mechanism of prostate cancer progression.This review focused on the role of various ncRNAs in prostate cancer and the association between their expression andCRPC.

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