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PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).ORCID iD: 0000-0003-0155-7639
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
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2022 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 798590Article in journal (Refereed) Published
Abstract [en]

PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022. Vol. 10, article id 798590
Keywords [en]
androgen receptor (AR), castration-resistant prostate cancer (CRPC), cyclin-dependent kinase (CDK), matrix metalloproteinases 9 (MMP9) PIP5K1α, phosphatidylinositol 4-phosphate 5 kinase (PIP5K1α), targeted therapy
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-193614DOI: 10.3389/fcell.2022.798590ISI: 000780059400001PubMedID: 35386201Scopus ID: 2-s2.0-85128078251OAI: oai:DiVA.org:umu-193614DiVA, id: diva2:1650455
Funder
EU, Horizon 2020, 721297Swedish Childhood Cancer Foundation, TJ2015-0097Swedish Cancer Society, CAN-2017-381Swedish Research Council, 2019-01318The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2013-5595The Kempe FoundationsCancerforskningsfonden i NorrlandAvailable from: 2022-04-07 Created: 2022-04-07 Last updated: 2023-05-23Bibliographically approved
In thesis
1. Utility of novel drug targets for treatment of metastatic cancer
Open this publication in new window or tab >>Utility of novel drug targets for treatment of metastatic cancer
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Användande av nya mål för läkemedel för behandling av metastaserande cancer
Abstract [en]

Metastasis is the leading cause of cancer death because of a lack of early diagnosis tools and efficient treatment drugs. The lipid kinase phosphatidylinositol 4-phosphate 5 kinase (PIP5K1α) has been shown to play a vital role in the PI3K/AKT and KRAS signaling pathways. My PhD work, therefore, aims: (i) to study the role of PIP5K1α as a potential target for cancer treatment and the utility of its inhibitor ISA-2011B for the treatment of castration-resistant prostate cancer (CRPC) and pancreatic cancer, (ii) to establish genetically engineered mouse models and murine syngeneic models to recapitulate pancreatic cancer progression and test targeted anticancer drugs, (iii)  to utilize the state-of-the-art molecularly imprinting technique for cancer biomarker detection.

My thesis work has shown a clear inhibitory effect of ISA-2011B on human CRPC cell lines C4-2, DU145, and PC-3. The siRNA-mediated downregulation of PIP5K1α and ISA-2011B treatments both showed inhibition of the in vitro growth in all three cell lines. The PC-3 cell and its xenograft tumor can be inhibited by tamoxifen or ISA-2011B treatment alone, and a combination treatment from both compounds can selectively block the ERα and PIP5K1α/AKT network. The results, therefore, suggest that it is possible to treat CRPC by targeting PIP5K1α/AKT and ERα pathways.

We established the KPC [Krastm4Tyj Trp53tm1Brn Tg(Pdx1-Cre/Esr1*)] mouse model, in which spontaneous pancreatic ductal adenocarcinoma (PDAC) develops under tamoxifen induction. Three PDAC cell lines bearing KRASG12D and P53 mutations from spontaneous tumors were established and characterized. ISA-2011B in vitro treatment on those cell lines showed that KRASG12D and pErk were significantly decreased in at least one of the cell lines. It suggests that PIP5K1α is a potential target, and its inhibitor ISA-2011B is a promising drug for treating KRAS-mutated PDAC. The syngeneic PDAC model was also prepared by subcutaneous injection of the three cell lines back into the KPC mice, which will be used as an in vivo model to study the function of PIP5K1α in PDAC further.

We developed molecularly imprinted polymers (MIPs) for the potential biomarker Neu5Acα2-6GalNAcα-O-Ser/Thr (STn), as well as the non-imprinted polymers(NIPs) as a control. We identified human PDAC cell lines CFPAC-1 and BxPC-3 are STn-positive and -negative cells, respectively. Although STn-MIPs have a higher affinity than NIPs to both cancer cell lines, STn-MIPs cannot differentiate the STn-positive CFPAC-1 cells from the STn-negative BxPC-3 cells. It remains challenging to apply MIPs to detect biological molecules.

Our data provide a novel therapeutic strategy to treat advanced cancers such as CRPC and KRAS-mutated PDAC by targeting PIP5K1α-associate PI3K/AKT and/or KRAS signaling pathways.

Abstract [sv]

Cancerspridning är den vanligaste orsaken till dödlighet. Det saknar förförande biomedicinska och diagnostiska metoder för tidigt upptäckten av cancer samt finns inte många effektiva och skrädd-sydda läkemedel. Lipidkinas såsom fosfatidylinositol 4-fosfat 5 kinas (PIP5K1α) har en viktig roll i styra cancer-specifika signalvägar PI3K/AKT och KRAS som ge upphov till cancerspridning. Målen för min doktorands forskningsprojekt är: (i) att studera rollen av PIP5K1α som ett potentiellt mål-protein i cancerspridning och testa PIP5K1α-hämmare ISA-2011B som läkemedel för att behandla aggressiva prostatacancer och bukspottkörtelcancer som är mycket dödliga cancertyper. (ii) att etablera genetiskt modifierade musmodeller som bära genetiska förändringar likande bukspottkörtelcancer i människor. Använda dessa musmodeller för att testa nya läkemedel för riktade behandling. (iii) att använda nya tekniken för att utveckla biomarkör för att upptäckten av cancer i tidigt fas.

Vi har visat att PIP5K1α-hämmare ISA-2011B ha goda och specifika effekter på prostatacancer celler. Behandling av cancerceller genom att hämma PIP5K1α gen- och protein-uttrycket led till cancercellens dödlighet och hämning av cancertillväxten i musmodeller och i cell-baserade modeller. Vidare har vi visade att läkemedel såsom östrogen-hämmare tamoxifen kan användas i kombination med ISA-2011B för att förhindra tumörtillväxt genom att selektivt blockera cancer signalvägar associerade med ERα, PIP5K1α/AKT-nätverket. Våra Resultat tyder på att det är möjligt att behandla prostatacancer genom att rikta in sig på PIP5K1α/AKT cancer-nätverket och/eller östrogen-vägen.

Vi etablerade genetiskt modifierade musmodeller som bära genetiska förändringar likande bukspottkörtelcancer i patienter. Vi testade effekt av ISA-2011B på tumörceller som odlade från tumör i dessa musmodeller. Vi har visat att ISA-2011B behandling led till minskade uttrycket av cancersignalvägar såsom KRASG12D och pErk. Våra resultat tyder på att PIP5K1α är ett lovande mål-protein, och dess hämmare ISA-2011B är ett potentiellt läkemedel för behandling av KRAS-muterad bukspottkörtelcancer. 

Vi utvecklade potentiella biomarkören som heter molekylärt präglade polymerer (MIPs) Neu5Acα2-6GalNAcα-O-Ser/Thr (STn). Vi visade att MIPs med STn kan känna igen cancerceller framförallt aggressiva bukspottkörtelcancer celler. Vi hoppas att STn-MIPs som nya biomarkör kan utvecklas vidare för att kunna upptäcka cancerceller i blodet, eftersom cancerceller i blodet har mycket högre halter av STn men inte normala blodceller. På så sätt patienter med risk att få eller ha bukspottkörtelcancer i tidig stadium kan få tidig diagnostik. 

Sammanfattningsvis våra studier kan bidra till en ny terapeutisk strategi för att behandla avancerad cancer och kan rikta in cancer-specifika PIP5K1α-associerade PI3K/AKT och KRAS-signalvägar.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2022. p. 36
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2179
Keywords
Metastatic cancer, castration-resistant prostate cancer, pancreatic ductal adenocarcinoma, target therapy, PIP5K1α, KRAS, molecularly imprinted polymers
National Category
Cancer and Oncology
Research subject
Oncology; Molecular Biology; Medical Cell Biology
Identifiers
urn:nbn:se:umu:diva-193617 (URN)978-91-7855-781-3 (ISBN)978-91-7855-782-0 (ISBN)
Public defence
2022-05-06, Hörsal 933, Unod B9, Norrlands universitetssjukhus, Umeå, 09:00 (English)
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Supervisors
Available from: 2022-04-14 Created: 2022-04-11 Last updated: 2022-04-11Bibliographically approved

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Wang, TianyanSarwar, MartuzaGreen, TamiSemenas, JuliusAmjad, AliHubert, MadlenChen, SaGrundström, ThomasLundmark, RichardGunhaga, LenaPersson, Jenny L.

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Wang, TianyanSarwar, MartuzaGreen, TamiSemenas, JuliusAmjad, AliHubert, MadlenChen, SaGrundström, ThomasLundmark, RichardGunhaga, LenaPersson, Jenny L.
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