LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer
| العنوان: | LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer |
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| المؤلفون: | Kavita Shah, Dung N. Nguyen, Moloud Aflaki Sooreshjani, Kumar Nikhil, Mohini Kamra, Dinesh Kumar |
| المصدر: | Cancers Volume 13 Issue 10 Cancers, Vol 13, Iss 2324, p 2324 (2021) |
| بيانات النشر: | MDPI, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, medicine.medical_treatment, Biology, urologic and male genital diseases, Article, Targeted therapy, law.invention, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Downregulation and upregulation, law, medicine, PTEN, castration-resistant prostate cancer, Protein kinase B, RC254-282, NKX3.1, urogenital system, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, Crosstalk (biology), LIMK2, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Phosphorylation, Suppressor |
| الوصف: | Simple Summary Prostate cancer is the principal cause of cancer-related mortality in men. While localized tumors can be successfully treated by orchiectomy or medical castration, most of the patients ultimately progress to the castration-resistant prostate cancer (CRPC) stage, which is incurable at present. Thus, uncovering the underlying mechanisms that cause CRPC could result in promising therapeutics. Our laboratory has identified LIMK2 kinase as an actionable target for CRPC. LIMK2 is vastly expressed in CRPC but minimally in normal prostates. LIMK2 knockout mice are healthy, indicating that LIMK2 inhibition should have minimal toxicity. LIMK2 is also expressed in other aggressive cancers; however, the molecular mechanisms leading to malignancy remain mostly unknown. This study identified that LIMK2 downregulates a prostate-specific tumor suppressor protein-NKX3.1 using two mechanisms. NKX3.1 loss is strongly associated with prostate cancer. Thus, LIMK2 inhibitor provides a powerful opportunity to rescue NKX3.1 loss, thereby preventing and/or delaying prostate cancer progression. Abstract NKX3.1’s downregulation is strongly associated with prostate cancer (PCa) initiation, progression, and CRPC development. Nevertheless, a clear disagreement exists between NKX3.1 protein and mRNA levels in PCa tissues, indicating that its regulation at a post-translational level plays a vital role. This study identified a strong negative relationship between NKX3.1 and LIMK2, which is critical in CRPC pathogenesis. We identified that NKX3.1 degradation by direct phosphorylation by LIMK2 is crucial for promoting oncogenicity in CRPC cells and in vivo. LIMK2 also downregulates NKX3.1 mRNA levels. In return, NKX3.1 promotes LIMK2’s ubiquitylation. Thus, the negative crosstalk between LIMK2-NKX3.1 regulates AR, ARv7, and AKT signaling, promoting aggressive phenotypes. We also provide a new link between NKX3.1 and PTEN, both of which are downregulated by LIMK2. PTEN loss is strongly linked with NKX3.1 downregulation. As NKX3.1 is a prostate-specific tumor suppressor, preserving its levels by LIMK2 inhibition provides a tremendous opportunity for developing targeted therapy in CRPC. Further, as NKX3.1 downregulates AR transcription and inhibits AKT signaling, restoring its levels by inhibiting LIMK2 is expected to be especially beneficial by co-targeting two driver pathways in tandem, a highly desirable requisite for developing effective PCa therapeutics. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a67af7c409af54d06a7f66d169506e3dTest http://europepmc.org/articles/PMC8151535Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a67af7c409af54d06a7f66d169506e3d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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