Upregulation of ATP Binding Cassette Subfamily C Member 5 facilitates Prostate Cancer progression and Enzalutamide resistance via the CDK1-mediated AR Ser81 Phosphorylation Pathway

Ji, Guangjie; He, Shiming; Huang, Cong; Gong, Yanqing; Li, Xuesong; Zhou, Liqun

doi:10.7150/ijbs.59559

Cited by 14 publications

(16 citation statements)

References 48 publications

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“…It currently remains unclear whether MRP5 is a NANOG downstream gene in PCSCs; however, it was not included among the 6490 target genes of the NANOG transcription factor obtained from the ChEP transcriptional factor targets dataset. Furthermore, Ji et al (2021) recently showed that the high expression of MRP5 reduced the sensitivity of LNCaP spheroids to EZT [37]. However, the present study showed no significant changes in antiandrogen resistance in LNCaP spheroids treated with MK571 (Supplementary Figure S3E,F).…”

Section: Discussioncontrasting

confidence: 49%

KCa1.1 K+ Channel Inhibition Overcomes Resistance to Antiandrogens and Doxorubicin in a Human Prostate Cancer LNCaP Spheroid Model

Ohya

Kajikuri

Endo

et al. 2021

IJMS

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Several types of K+ channels play crucial roles in tumorigenicity, stemness, invasiveness, and drug resistance in cancer. Spheroid formation of human prostate cancer (PC) LNCaP cells with ultra-low attachment surface cultureware induced the up-regulation of cancer stem cell markers, such as NANOG, and decreased the protein degradation of the Ca2+-activated K+ channel KCa1.1 by down-regulating the E3 ubiquitin ligase, FBXW7, compared with LNCaP monolayers. Accordingly, KCa1.1 activator-induced hyperpolarizing responses were larger in isolated cells from LNCaP spheroids. The pharmacological inhibition of KCa1.1 overcame the resistance of LNCaP spheroids to antiandrogens and doxorubicin (DOX). The protein expression of androgen receptors (AR) was significantly decreased by LNCaP spheroid formation and reversed by KCa1.1 inhibition. The pharmacological and genetic inhibition of MDM2, which may be related to AR protein degradation in PC stem cells, revealed that MDM2 was responsible for the acquisition of antiandrogen resistance in LNCaP spheroids, which was overcome by KCa1.1 inhibition. Furthermore, a member of the multidrug resistance-associated protein subfamily of ABC transporters, MRP5 was responsible for the acquisition of DOX resistance in LNCaP spheroids, which was also overcome by KCa1.1 inhibition. Collectively, the present results suggest the potential of KCa1.1 in LNCaP spheroids, which mimic PC stem cells, as a therapeutic target for overcoming antiandrogen- and DOX-resistance in PC cells.

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Section: Discussioncontrasting

confidence: 49%

KCa1.1 K+ Channel Inhibition Overcomes Resistance to Antiandrogens and Doxorubicin in a Human Prostate Cancer LNCaP Spheroid Model

Ohya

Kajikuri

Endo

et al. 2021

IJMS

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“… [58] ABCC5 is significantly overexpressed in prostate cancer, in which its expression is positively correlated with cell proliferation, migration, and invasion. [29] In esophageal squamous cell carcinoma, ABCC7 overexpression can activate the p38 signaling pathway; this activation is associated with a good prognosis. [59] ABCC8 mRNA expression is a new independent prognostic indicator of glioma: high expression is associated with longer survival.…”

Section: Discussionmentioning

confidence: 99%

“…ABCC4 is overexpressed in colorectal cancer, in which it may be associated with phenotypic transition, which regulates cell migration in a cyclic nucleotide-dependent manner [58] . ABCC5 is significantly overexpressed in prostate cancer, in which its expression is positively correlated with cell proliferation, migration, and invasion [29] . In esophageal squamous cell carcinoma, ABCC7 overexpression can activate the p38 signaling pathway; this activation is associated with a good prognosis [59] .…”

Section: Discussionmentioning

confidence: 99%

Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma

et al. 2022

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“…This transcriptional increase in total AR pre-mRNA may be sufficient to increase the mRNA and protein expression of AR-V7 owning a cryptic exon 3 (CE3), which circumvents the enzalutamide-mediated blockage of nuclear translocation of the ligand-receptor complex and activate AR-V7-relied downstream targets, like SREBF1, to maintain the proliferation activity of PCa cells, increases drug resistance [ 36 ]. A recently published finding has reported that ABCC5 exerted a protumor effect to promote the phosphorylation of AR at Ser81 by CDK1 and activated the AR downstream target genes and promoted the malignant progression and enzalutamide resistance of prostate cancer [ 37 ], although it was unclear if ABCC5 transcriptionally promoted the AR expression and how it improved the drug resistance. Our findings focused on the ABCC5-mediated enzalutamide resistance and indicated that ABCC5 regulates the activity of NF-κB-p65 and generation of AR transcripts, further explaining the potential AR upstream mechanism of ABCC5-mediated enzalutamide resistance, indicating that future development of specific ABCC5 inhibitors may be a promising strategy to target prostate cancer AR-antagonist resistance.…”

Section: Discussionmentioning

confidence: 99%

Non-drug efflux function of ABCC5 promotes enzalutamide resistance in castration-resistant prostate cancer via upregulation of P65/AR-V7

et al. 2022

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Drug resistance is responsible for castration-resistant prostate cancer (CRPC)-associated mortality. While ATP binding cassette subfamily C member 5 (ABCC5) has been reported to regulate multiple drug resistance, its drug-efflux function may not be the main reason underlying resistance to enzalutamide, an androgen receptor inhibitor. Here, we aimed to determine whether the non-drug efflux function of ABCC5 affects enzalutamide resistance. The ABCC5 expression data in patients with prostate cancer (PCa) were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus, and their correlation with disease prognosis was analyzed. Immunohistochemical staining was performed on a cohort of 80 patient samples. Proliferation of enzalutamide-resistant 22RV1 and C4-2B cells was investigated using CCK-8, EdU, and colony formation assays. The effect of ABCC5 silencing on enzalutamide resensitization was evaluated in vitro and in vivo. Functional assays indicated that ABCC5 depletion resensitized enzalutamide-resistant cells to inhibit cell growth and impeded xenograft tumor proliferation. Mechanistically, luciferase and ChIP assays confirmed that P65 regulated AR expression and activity by binding to its promoter, while ABCC5-mediated resistance effected by AR-V7 (one of the widely studied AR splicing variants that meditate AR antagonist resistance) upregulation could be reversed by P65 knockdown. Furthermore, activation of the NF-κB pathway reversed the effects of ABCC5 knockdown by extra AR-V7 expression. Thus, ABCC5 might be a novel target for enzalutamide-resistant CRPC treatment.

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Upregulation of ATP Binding Cassette Subfamily C Member 5 facilitates Prostate Cancer progression and Enzalutamide resistance via the CDK1-mediated AR Ser81 Phosphorylation Pathway

Cited by 14 publications

References 48 publications

KCa1.1 K+ Channel Inhibition Overcomes Resistance to Antiandrogens and Doxorubicin in a Human Prostate Cancer LNCaP Spheroid Model

KCa1.1 K+ Channel Inhibition Overcomes Resistance to Antiandrogens and Doxorubicin in a Human Prostate Cancer LNCaP Spheroid Model

Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma

Non-drug efflux function of ABCC5 promotes enzalutamide resistance in castration-resistant prostate cancer via upregulation of P65/AR-V7

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