A cyclic peptide retards the proliferation of DU145 prostate cancer cells in vitro and in vivo through inhibition of FGFR2

Zhang, Hongjie; Ouyang, Man; Wang, Hailong; Zhang, Bihui; Guang, Wenhua; Liu, Ruiwu; Li, Xiaocen; Shih, Tsung-Chieh; Li, Zhixin; Cao, Jieqiong; Meng, Qiling; Su, Zijian; Ye, Jinshao; Liu, Feng; An, Hongyu; Chen, Xiaojia

doi:10.1002/mco2.48

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…We have focused on investigating the roles of FGFs and FGFRs for years [ 37 – 41 ] and recently demonstrated that an endogenous FGFR2 inhibitory oligopeptide (P5), which is degraded from the basic fibroblast growth factor (bFGF, also known as FGF2) in vivo, effectively inhibits its downstream signalling. Importantly, P5 is a naturally occurring endogenous molecule that exhibits biological activities without terrible side effects [ 42 ]. This discovery of mild FGFR inhibitors with negligible toxicity will broaden the possible applications, especially for nonlethal inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Hyaluronic acid-FGF2-derived peptide bioconjugates for suppression of FGFR2 and AR simultaneously as an acne antagonist

Zhang

Cao

et al. 2023

J Nanobiotechnol

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Acne is a chronic skin condition that has serious consequences for mental and social well-being because it frequently occurs on the face. Several acne treatment approaches have commonly been used but have been hampered by side effects or weak activity. Thus, the investigation of the safety and efficacy of anti-acne compounds is of considerable medical importance. Herein, an endogenous peptide (P5) derived from fibroblast growth factors 2 (FGF2) was conjugated to the polysaccharide hyaluronic acid (HA) to generate the bioconjugate nanoparticle HA-P5, which suppresses fibroblast growth factor receptors (FGFRs) to significantly rehabilitate acne lesions and reduce sebum accumulation in vivo and in vitro. Moreover, our results show that HA-P5 inhibits both fibroblast growth factor receptor 2 (FGFR2) and androgen receptor (AR) signalling in SZ95 cells, reverses the acne-prone transcriptome, and decreases sebum secretion. Furthermore, the cosuppression mechanism revealed that HA-P5 blocks FGFR2 activation, as well as the YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) downstream molecules, including an N6-methyladenosine (m6A) reader that facilitates AR translation. More importantly, a significant difference between HA-P5 and the commercial FGFR inhibitor AZD4547 is that HA-P5 does not trigger the overexpression of aldo-keto reductase family 1 member C3 (AKR1C3), which blocks acne treatment by catalyzing the synthesis of testosterone. Overall, we demonstrate that a polysaccharide-conjugated and naturally derived oligopeptide HA-P5 can alleviate acne and act as an optimal FGFR2 inhibitor and reveal that YTHDF3 plays a crucial role in signalling between FGFR2 and AR. Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

Hyaluronic acid-FGF2-derived peptide bioconjugates for suppression of FGFR2 and AR simultaneously as an acne antagonist

Zhang

Cao

et al. 2023

J Nanobiotechnol

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“…FGFR2, a receptor for the cytokine FGF10, is a key regulator of bone development and cancer. 48 Deletion of Fgfr2 isoforms results in osteogenesis dysfunction, suggesting its crucial role in bones. 3,[49][50][51] In this study, we discovered that FGFR2 is a potential substrate of OTUB1.…”

Section: Discussionmentioning

confidence: 99%

OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2

Chu

Ding

et al. 2023

Sig Transduct Target Ther

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Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Dysregulation of this process leads to multiple diseases, including osteoporosis. However, the underlying molecular mechanisms are not fully understood. Here, we show that the global and conditional osteoblast knockout of a deubiquitinase Otub1 result in low bone mass and poor bone strength due to defects in osteogenic differentiation and mineralization. Mechanistically, the stability of FGFR2, a crucial regulator of osteogenesis, is maintained by OTUB1. OTUB1 attenuates the E3 ligase SMURF1-mediated FGFR2 ubiquitination by inhibiting SMURF1’s E2 binding. In the absence of OTUB1, FGFR2 is ubiquitinated excessively by SMURF1, followed by lysosomal degradation. Consistently, adeno-associated virus serotype 9 (AAV9)-delivered FGFR2 in knee joints rescued the bone mass loss in osteoblast-specific Otub1-deleted mice. Moreover, Otub1 mRNA level was significantly downregulated in bones from osteoporotic mice, and restoring OTUB1 levels through an AAV9-delivered system in ovariectomy-induced osteoporotic mice attenuated osteopenia. Taken together, our results suggest that OTUB1 positively regulates osteogenic differentiation and mineralization in bone homeostasis by controlling FGFR2 stability, which provides an optical therapeutic strategy to alleviate osteoporosis.

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“…Although exogenous designed peptites have been shown promising therapeutic potentials [ 26 ], our understanding on cellular endogenous micropeptides remains very limited. In this study, we found that LINC00998, a gene initially annotated as a lncRNA, encodes a membrane‐integrated micropeptide named SMIM30.…”

Section: Discussionmentioning

confidence: 99%

LINC00998‐encoded micropeptide SMIM30 promotes the G1/S transition of cell cycle by regulating cytosolic calcium level

et al. 2022

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The biological functions of short open reading frame (sORF)‐encoded micropeptides remain largely unknown. Here, we report that LINC00998 , a previously annotated lncRNA, was upregulated in multiple cancer types and the sORF on LINC00998 encoded a micropeptide named SMIM30. SMIM30 was localized in the membranes of the endoplasmic reticulum (ER) and mitochondria. Silencing SMIM30 inhibited the proliferation of hepatoma cells in vitro and suppressed the growth of tumor xenografts and N‐nitrosodiethylamine‐induced hepatoma. Overexpression of the 5′UTR‐sORF sequence of LINC00998 , encoding wild‐type SMIM30, enhanced tumor cell growth, but this was abolished when a premature stop codon was introduced into the sORF via single‐base deletion. Gain‐ and loss‐of‐function studies revealed that SMIM30 peptide but not LINC00998 reduced cytosolic calcium level, increased CDK4, cyclin E2, phosphorylated‐Rb and E2F1, and promoted the G1/S phase transition and cell proliferation. The effect of SMIM30 silencing was attenuated by a calcium chelator or the agonist of sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. These findings suggest a novel function of micropeptide SMIM30 in promoting G1/S transition and cell proliferation by enhancing SERCA activity and reducing cytosolic calcium level.

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A cyclic peptide retards the proliferation of DU145 prostate cancer cells in vitro and in vivo through inhibition of FGFR2

Cited by 8 publications

References 42 publications

Hyaluronic acid-FGF2-derived peptide bioconjugates for suppression of FGFR2 and AR simultaneously as an acne antagonist

Hyaluronic acid-FGF2-derived peptide bioconjugates for suppression of FGFR2 and AR simultaneously as an acne antagonist

OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2

LINC00998‐encoded micropeptide SMIM30 promotes the G1/S transition of cell cycle by regulating cytosolic calcium level

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