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Non-canonical TGFb signaling pathways in prostate cancer
Umeå University, Faculty of Medicine, Department of Medical Biosciences. (Marene Landstrom)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer is the second leading cause of cancer-related death in men in the Western world. Deregulation of transforming growth factor β (TGFβ) signaling pathway is frequently detected in prostate cancer and contributes to tumor growth, migration, and invasion. In normal tissue and the early stages of cancer, TGFβ acts as a tumor suppressor by regulating proliferation, differentiation, and apoptosis. In later stages of cancer, TGFβ acts as a tumor promoter by inducing angiogenesis, tumor invasion, and migration. Thus, it is important to investigate the molecular mechanisms behind the tumor-promoting effects of TGFβ, which is the topic of this thesis.

 

The tumor necrosis factor receptor–associated factor 6 (TRAF6) controls non-canonical TGFβ signals due to its enzymatic activity, causing polyubiquitination of the cell membrane–bound, serine/threonine kinase TGFβ type I receptor (TβRI) and its subsequent cleavage in the extracellular domain by tumor necrosis factor a–converting enzyme (TACE) in a protein kinase C ζ (PKCζ)-dependent manner. TRAF6 also recruits the active g-secretase complex to the TβRI, resulting in a second cleavage in the transmembrane region and the liberation of the TβRI intracellular domain (TβRI-ICD), which enters the nucleus, where it associates with the transcriptional co-regulator p300. In Paper I, the aim was to elucidate by which mechanisms TβRI-ICD enters the nucleus. We found that the endocytic adaptor protein APPL1 interacts with TβRI and PKCζ. APPL proteins are required for TβRI translocation from endosomes to the nucleus via microtubules in a TRAF6-dependent manner. Moreover, APPL proteins are important for TGFβ-induced cell invasion, and high levels of APPL1 are detected by immunohistochemistry in prostate cancer. Finally, we demonstrated that the APPL1–TβRI complex visualized with the in situ proximity ligation assay (PLA) correlates with Gleason score, indicating that it might be a novel prognostic marker for aggressive prostate cancer. In Paper II, the aim was to explore by which mechanisms TGFβ causes activation of the AKT pathway, which regulates migration and therapy resistance of cancer cells. We found that the E3 ligase activity of TRAF6 induces Lys63-linked polyubiquitination of p85α upon TGFβ stimulation, resulting in plasma membrane recruitment, Lys63-linked polyubiquitination, and subsequent activation of AKT. Moreover, the TRAF6 and PI3K/AKT pathway were found to be crucial for the TGFβ-induced migration. Importantly, we demonstrated, by PLA, a correlation between Lys63-linked polyubiquitination of p85α and aggressive prostate cancer in tissue sections from patients with prostate cancer. In Paper III, the aim was to investigate the mechanisms for TGFβ-induced activation of PKCζ and the role of PKCζ in tumor regression. We found that TRAF6 caused Lys63-linked polyubiquitination of PKCζ. By using two novel chemical compounds that inhibit PKCζ, we demonstrated that PKCζ is crucial for prostate cancer cell survival and invasion. In Paper IV, the aim was to investigate further the target genes for the nuclear TβRI-ICD-APPL1 complex identified in Paper I. We provide evidence that APPL proteins and the TGFβ signaling pathway are important for cell proliferation. In summary, the results reported in this thesis suggest the potential usefulness of the identified signaling components of the tumor-promoting effects of TGFβ as drug targets and biomarkers for aggressive prostate cancer. 

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 55+4 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1849
Keyword [en]
TGFβ, TβRI, TRAF6, ubiquitination, APPL1, p85, AKT, PKCζ
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-127694ISBN: 978-91-7601-580-3 (print)OAI: oai:DiVA.org:umu-127694DiVA: diva2:1047676
Public defence
2016-12-16, E04, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-11-25 Created: 2016-11-18 Last updated: 2016-11-24Bibliographically approved
List of papers
1. APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain
Open this publication in new window or tab >>APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, 279-292 p.Article in journal (Refereed) Published
Abstract [en]

The multifunctional cytokine transforming growth factor-beta (TGF beta) is produced by several types of cancers, including prostate cancer, and promote tumour progression in autocrine and paracrine manners. In response to ligand binding, the TGF beta type I receptor (T beta RI) activates Smad and non-Smad signalling pathways. The ubiquitin-ligase tumour necrosis factor receptor-associated factor 6 (TRAF6) was recently linked to regulate intramembrane proteolytic cleavage of the T beta RI in cancer cells. Subsequently, the intracellular domain (ICD) of T beta RI enters in an unknown manner into the nucleus, where it promotes the transcription of pro-invasive genes, such as MMP2 and MMP9. Here we show that the endocytic adaptor molecules APPL1 and APPL2 are required for TGF beta-induced nuclear translocation of T beta RI-ICD and for cancer cell invasiveness of human prostate and breast cancer cell lines. Moreover, APPL proteins were found to be expressed at high levels in aggressive prostate cancer tissues, and to be associated with T beta RI in a TRAF6-dependent manner. Our results suggest that the APPL-T beta RI complex promotes prostate tumour progression, and may serve as a prognostic marker.

Keyword
APPL proteins, prostate cancer, signal transduction, tumour necrosis factor receptor-associated factor 6, transforming growth factor beta
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-117841 (URN)10.18632/oncotarget.6346 (DOI)000369950300023 ()26583432 (PubMedID)
Available from: 2016-03-30 Created: 2016-03-04 Last updated: 2016-11-18Bibliographically approved
2. TGFβ promotes prostate cancer cell migration via TRAF6-mediated ubiquitination of p85α causing activation of the PI3K/AKT pathway.
Open this publication in new window or tab >>TGFβ promotes prostate cancer cell migration via TRAF6-mediated ubiquitination of p85α causing activation of the PI3K/AKT pathway.
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(English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145Article in journal (Other academic) Submitted
Keyword
TRAF6, AKT, p85
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-127688 (URN)
Funder
Knut and Alice Wallenberg Foundation, KAW 2012.0090Swedish Cancer Society, CAN 2014/674
Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2016-11-24
3. TGFβ-induced activation of PKCζ confers invasive prostate cancer growth
Open this publication in new window or tab >>TGFβ-induced activation of PKCζ confers invasive prostate cancer growth
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

One of the hallmarks for aggressivecancer is the capability oftumor cells to become invasive and metastatic. Cancer cells and tumor stromal cells oftenproduce high levels of transforming growth factor b(TGFb) which initiates intracellular signaling pathways in cancer cells in a contextualdependentmanner. Atypical protein kinase C z(PKCz) is a multifunctional protein which maintains cell polarity of normal epithelial cells, while itsaberrantexpression and activation is linked to tumor progression. Tumor necrosisfactor receptor-associated factor6 (TRAF6) is amplified in lung cancer and caninitiate intracellular oncogenic signals. In prostate cancer cellsTRAF6 promotesligand-induced proteolytic cleavage of TGFbtype I receptor(TbRI), and nuclear translocation of its intracellular domain (ICD) to confer invasion of cancer cells. Here we report our novel findingsthat PKCzharboursa TRAF6 consensus binding site and that TRAF6 causes Lys63-linked polyubiquitination of PKCz. TGFb-induced phosphorylationof PKCzis dependent on TRAF6in prostate cancer cells and we have investigated the potential usefulness of twodifferent inhibitors of PKCzas potential novel anti-cancer drugs.

Keyword
TRAF6, PKCζ, TGFβ
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-127692 (URN)
Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2017-02-08
4. TGFb type I receptor and endosomal APPL regulate AURKB during mitosis and cytokinesis
Open this publication in new window or tab >>TGFb type I receptor and endosomal APPL regulate AURKB during mitosis and cytokinesis
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The cytokine transforming growth factor b(TGFb) suppressescell proliferationand promotesapoptosis1. It signalsvia specific serine/threonine kinase receptors, i.e.TGFbtype I (TbRI) and type II (TbRII) receptors2,3,causing growth arrest of normal epithelial cells. However, TGFbis often overexpressed inadvanced cancers,and promotes proliferation of tumour cells and their invasion. The intracellular domain (ICD) of TbRI is cleaved offin cancer cells,and is translocated to the nucleus in an APPL1/2-dependent manner, drivingan invasiveness program4.The specific mechanism(s) whereby cancer cells escape pro-apoptotic signals induced by TGFbremainspoorly understood. Here, we report that TbRI and APPL1/2 proteins orchestrate this escape via the pro-survival protein survivin and Aurora kinase B (AURKB), a key regulatorof mitosis and chromosomal stability5. We show that TbRI and APPL1/2 control expression of AURKB and that TbRI-ICDand AURKB form a complex during the telophase in PC-3Uprostate cancerand KELLY neuroblastomacells. APPL1/2 and TbRI also form a complex with survivin, a pro-survival protein. The identified TbRI–AURKB-survivinpathwayrepresents a novel function for TbRI to promote survival and cell division of cancer cells.

National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-127693 (URN)
Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2017-02-08

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