bims-polyam 2021-05-16 papers

Issue of 2021–05–16
five papers selected by
Sebastian J. Hofer, University of Graz

J Invest Dermatol. 2021 May 10. pii: S0022-202X(21)01219-7. [Epub ahead of print]

The polyamine regulator AMD1 up-regulates spermine levels to drive epidermal differentiation.

Anisa B Rahim, Hui Kheng Lim, Christina Yan Ru Tan, Li Jia, Vonny Ivon Leo, Takeshi Uemura, Jonathan Hardman-Smart, John E A Common, Thiam Chye Lim, Sophie Bellanger, Ralf Paus, Kazuei Igarashi, Henry Yang, Leah A Vardy.

Maintaining tissue homeostasis depends on a balance of cell proliferation, differentiation and apoptosis. Within the epidermis the levels of the polyamines putrescine, spermidine and spermine are altered in many different skin conditions yet their role in epidermal tissue homeostasis is poorly understood. We identify the polyamine regulator, AMD1, as a crucial regulator of keratinocyte differentiation. AMD1 protein is upregulated on differentiation and highly expressed in the suprabasal layers of the human epidermis. During keratinocyte differentiation, elevated AMD1 promotes decreased putrescine and increased spermine levels. Knockdown/inhibition of AMD1 results in reduced spermine levels and inhibition of keratinocyte differentiation. Supplementing AMD1-knockdown keratinocytes with exogenous spermidine/spermine rescued aberrant differentiation. We show that the polyamine shift is critical for the regulation of key transcription factors and signalling proteins that drive keratinocyte differentiation including KLF4 and ZNF750. These findings demonstrate that human keratinocytes use controlled changes in polyamine levels to modulate gene expression to drive cellular behaviour changes. Modulation of polyamine levels during epidermal differentiation could impact skin barrier formation or be used in the treatment of hyper-proliferative skin disorders.

Keywords: AMD1; Differentiation; Epidermis; Keratinocyte; Polyamines; Skin Barrier; Spermine

DOI: https://doi.org/10.1016/j.jid.2021.01.039

Med Res Rev. 2021 May 10.

Natural products as geroprotectors: An autophagy perspective.

Stephen D Raj, David Y Fann, Esther Wong, Brian K Kennedy.

Over the past decade, significant attention has been given to repurposing Food and Drug Administration approved drugs to treat age-related diseases. In contrast, less consideration has been given to natural bioactive compounds. Consequently, there have been limited attempts to translate these compounds. Autophagy is a fundamental biological pathway linked to aging, and numerous strategies to enhance autophagy have been shown to extend lifespan. Interestingly, there are a number of natural products that are reported to modulate autophagy, and here we describe a number of them that activate autophagy through diverse molecular and cellular mechanisms. Among these, Urolithin A, Spermidine, Resveratrol, Fatty Acids and Phospholipids, Trehalose and Lithium are featured in detail. Finally, we outline possible strategies to optimise and increase the translatability of natural products, with the overall aim of delaying the ageing process and improving human healthspan.

Keywords: Urolithin A; ageing; autophagy; drug discovery; fatty acids and phospholipids; geroscience; lipids; lithium; natural products; resveratrol; spermidine; trehalose

DOI: https://doi.org/10.1002/med.21815

J Cell Sci. 2021 May 01. pii: jcs252767. [Epub ahead of print]134(9):

N1-acetylspermidine is a determinant of hair follicle stem cell fate.

Kira Allmeroth, Christine S Kim, Andrea Annibal, Andromachi Pouikli, Janis Koester, Maxime J Derisbourg, Carlos Andrés Chacón-Martínez, Christian Latza, Adam Antebi, Peter Tessarz, Sara A Wickström, Martin S Denzel.

Stem cell differentiation is accompanied by increased mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine and spermine, which are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translational control remains obscure. Here, we investigate the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. Compared to progenitor cells, HFSCs showed lower translation rates, correlating with reduced polyamine levels. Surprisingly, overall polyamine depletion decreased translation but did not affect cell fate. In contrast, specific depletion of natural polyamines mediated by spermidine/spermine N1-acetyltransferase (SSAT; also known as SAT1) activation did not reduce translation but enhanced stemness. These results suggest a translation-independent role of polyamines in cell fate regulation. Indeed, we identified N1-acetylspermidine as a determinant of cell fate that acted through increasing self-renewal, and observed elevated N1-acetylspermidine levels upon depilation-mediated HFSC proliferation and differentiation in vivo. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions. This article has an associated First Person interview with the first author of the paper.

Keywords: Cell fate; Hair follicle stem cells; Polyamines; mRNA translation

DOI: https://doi.org/10.1242/jcs.252767

Eur J Med Chem. 2021 Apr 26. pii: S0223-5234(21)00318-4. [Epub ahead of print]221 113469

A naphthalimide-polyamine conjugate preferentially accumulates in hepatic carcinoma metastases as a lysosome-targeted antimetastatic agent.

Jing Ma, Linrong Li, Kexin Yue, Zhansheng Zhang, Shihao Su, Yutong Chen, Lu Yu, Pengfei Zhang, Ruijuan Ma, Yingguang Li, Yinxia Ma, Huinan Jia, Chaojie Wang, Jiajia Wang, Songqiang Xie.

Disseminated tumors lead to approximately 90% of cancer-associated deaths especially for hepatocellular carcinoma (HCC), indicating the imperative need of antimetastatic drugs and the ineffectiveness of current therapies. Recently polyamine derivatives have been identified as a promising prospect in dealing with metastatic tumors. Herein, a novel class of naphthalimide-polyamine conjugates 8a-8d, 13a-13c, 17 and 21 were synthesized and the mechanism was further determined. The polyamine conjugate 13b displayed remarkably elevated anti-tumor and anti-metastatic effects (76.01% and 75.02%) than the positive control amonafide (46.91% and 55.77%) at 5 mg/kg in vivo. The underlying molecular mechanism indicated that in addition to induce DNA damage by up-regulating p53 and γH2AX, 13b also targeted lysosome to modulate polyamine metabolism and function in a totally different way from that of amonafide. Furthermore, the HMGB1/p62/LC3II/LC3I and p53/SSAT/β-catenin pathways were mainly involved in the inhibition of 13b-induced HCC metastasis by targeting polyamine transporters (PTs) overexpressed in HCC. At last, 13b down-regulated the concentrations of Put, Spd and Spm by modulating polyamine metabolism key enzymes SSAT and PAO, which favored the suppression of fast growing tumor cells. Taken together, our study implies a promising strategy for naphthalimide conjugates to treat terminal cancer of HCC by targeting autophagy and tumor microenvironment with reduced toxicities and notable activities.

Keywords: Hepatic carcinoma; Lysosome; Naphthalimide conjugates; Polyamine metabolism and function; Polyamine transporter

DOI: https://doi.org/10.1016/j.ejmech.2021.113469

Aging Cell. 2021 May 09. e13377

Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway.

Xiaoyu Liu, An Chen, Qingchun Liang, Xiulin Yang, Qianqian Dong, Mingwei Fu, Siyi Wang, Yining Li, Yuanzhi Ye, Zirong Lan, Yanting Chen, Jing-Song Ou, Pingzhen Yang, Lihe Lu, Jianyun Yan.

Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular calcification is a gene-regulated biological process resembling osteogenesis involving osteogenic differentiation. However, there is no efficient treatment available for vascular calcification so far. The natural polyamine spermidine has been demonstrated to increase life span and protect against cardiovascular disease. It is unclear whether spermidine supplementation inhibits vascular calcification in CKD. Alizarin red staining and quantification of calcium content showed that spermidine treatment markedly reduced mineral deposition in both rat and human vascular smooth muscle cells (VSMCs) under osteogenic conditions. Additionally, western blot analysis revealed that spermidine treatment inhibited osteogenic differentiation of rat and human VSMCs. Moreover, spermidine treatment remarkably attenuated calcification of rat and human arterial rings ex vivo and aortic calcification in rats with CKD. Furthermore, treatment with spermidine induced the upregulation of Sirtuin 1 (SIRT1) in VSMCs and resulted in the downregulation of endoplasmic reticulum (ER) stress signaling components, such as activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP). Both pharmacological inhibition of SIRT1 by SIRT1 inhibitor EX527 and knockdown of SIRT1 by siRNA markedly blocked the inhibitory effect of spermidine on VSMC calcification. Consistently, EX527 abrogated the inhibitory effect of spermidine on aortic calcification in CKD rats. We for the first time demonstrate that spermidine alleviates vascular calcification in CKD by upregulating SIRT1 and inhibiting ER stress, and this may develop a promising therapeutic treatment to ameliorate vascular calcification in CKD.

Keywords: SIRT1; aging; chronic kidney disease; endoplasmic reticulum stress; spermidine; vascular calcification

DOI: https://doi.org/10.1111/acel.13377