LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer.
LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer.
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DOI：
10.3390/cancers13102324
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发表时间：
2021-05-12
期刊：
影响因子：
5.2
通讯作者：
Shah K
中科院分区：
文献类型：
--
作者：
Sooreshjani MA;Nikhil K;Kamra M;Nguyen DN;Kumar D;Shah K
前列腺癌是男性癌症相关死亡的主要原因。虽然局部肿瘤可以通过睾丸切除术或药物去势成功治疗，但大多数患者最终进展到去势抵抗性前列腺癌（CRPC）阶段，目前无法治愈。因此，揭示导致CRPC的潜在机制可能会导致有希望的治疗方法。我们的实验室已经确定LIMK 2激酶为CRPC的可操作靶点。LIMK 2在CRPC中大量表达，但在正常前列腺中表达最低。LIMK 2敲除小鼠是健康的，表明LIMK 2抑制应该具有最小的毒性。LIMK 2也在其他侵袭性癌症中表达;然而，导致恶性肿瘤的分子机制仍然大部分未知。本研究证实LIMK 2通过两种机制下调前列腺特异性肿瘤抑制蛋白NKX 3.1。NKX3.1缺失与前列腺癌密切相关。因此，LIMK 2抑制剂提供了挽救NKX3.1损失的强大机会，从而预防和/或延迟前列腺癌进展。NKX3.1的下调与前列腺癌（PCa）的发生、进展和CRPC的发展密切相关。然而，在PCa组织中NKX3.1蛋白和mRNA水平之间存在明显的不一致，表明其在翻译后水平的调节起着至关重要的作用。这项研究确定了NKX3.1和LIMK 2之间的强负相关性，这在CRPC发病机制中至关重要。我们发现，通过LIMK 2直接磷酸化的NKX3.1降解对于促进CRPC细胞和体内的致癌性至关重要。LIMK 2还下调NKX3.1 mRNA水平。作为回报，NKX3.1促进LIMK 2的泛素化。因此，LIMK 2-NKX3.1之间的负串扰调节AR、ARv 7和AKT信号传导，促进侵袭性表型。我们还提供了NKX3.1和PTEN之间的新联系，两者都被LIMK 2下调。PTEN缺失与NKX3.1下调密切相关。由于NKX3.1是一种前列腺特异性肿瘤抑制因子，通过LIMK 2抑制来保持其水平为开发CRPC靶向治疗提供了巨大的机会。此外，由于NKX3.1下调AR转录并抑制AKT信号传导，通过抑制LIMK 2恢复其水平预计通过共靶向串联的两个驱动途径是特别有益的，这是开发有效的PCa治疗剂的高度期望的必要条件。
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. 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.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8.8
作者：
Bowen C;Ju JH;Lee JH;Paull TT;Gelmann EP
通讯作者：
Gelmann EP
影响因子：
82.9
作者：
Nagahara, H;Vocero-Akbani, AM;Dowdy, SF
通讯作者：
Dowdy, SF
影响因子：
4
作者：
Johnson, Emmanuel O.;Chang, Kuei-Hua;Shah, Kavita
通讯作者：
Shah, Kavita
影响因子：
11.2
作者：
Asatiani, E;Huang, WX;Gelmann, EP
通讯作者：
Gelmann, EP