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Background <p>Activin A/Smad signaling plays an important role in promoting cancer stemness and chemoresistance in pancreatic ductal adenocarcinoma (PDAC), however the precise regulation on the termination of this pathway has not been fully understood.</p> Methods <p>LncRNA <i>SLC7A11-AS1</i> interacting proteins were identified through RNA pull-down followed by LC-MS/MS. The protein interaction was analyzed by co-immunoprecipitation. The expressions of <i>SLC7A11-AS1</i> and activin A in tissue microarray were analyzed by FISH and immunofluerescence. Tumor xenograft mice models were established for in vivo experiments.</p> Results <p>Overexpression of <i>SLC7A11-AS1</i> enhanced the activin A-induced Smad2/3 phosphorylation and promoted cancer stemness properties in PDAC cells. Mechanically, <i>SLC7A11-AS1</i> interacts with scaffold protein RSL1D1. This interaction disrupts PPM1A myristoylation by suppressing the recruitment of PPM1A and myristoyltransferase NMT1 to RSL1D1, leading to prolonged activation of activin A/Smad signaling through the delay of Smad2/3 dephosphorylation. Co-overexpression of <i>SLC7A11-AS1</i> and activin A were found in pancreatic patients, and related with the extremely short survival periods. Knockdown of <i>SLC7A11-AS1</i> and blockade of activin A signaling significantly reduced gemcitabine resistance in PDAC in vitro and in vivo.</p> Conclusions <p><i>SLC7A11-AS1</i> contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation. Targeting both <i>SLC7A11-AS1</i> and activin A may offer a potential therapeutic strategy for overcoming gemcitabine resistance in PDAC.</p>

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SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation in pancreatic cancer

  • 期刊论文

  • 发表日期：

    2025年9月9日

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  • Mengmeng Li,
  • Zhicheng Zhang,
  • Qingzhu Yang,
  • Fei Wang,
  • Xuemei Huang,
  • Huan Nie,
  • Kai Li,
  • Huanjie Yang

摘要

Background

Activin A/Smad signaling plays an important role in promoting cancer stemness and chemoresistance in pancreatic ductal adenocarcinoma (PDAC), however the precise regulation on the termination of this pathway has not been fully understood.

Methods

LncRNA SLC7A11-AS1 interacting proteins were identified through RNA pull-down followed by LC-MS/MS. The protein interaction was analyzed by co-immunoprecipitation. The expressions of SLC7A11-AS1 and activin A in tissue microarray were analyzed by FISH and immunofluerescence. Tumor xenograft mice models were established for in vivo experiments.

Results

Overexpression of SLC7A11-AS1 enhanced the activin A-induced Smad2/3 phosphorylation and promoted cancer stemness properties in PDAC cells. Mechanically, SLC7A11-AS1 interacts with scaffold protein RSL1D1. This interaction disrupts PPM1A myristoylation by suppressing the recruitment of PPM1A and myristoyltransferase NMT1 to RSL1D1, leading to prolonged activation of activin A/Smad signaling through the delay of Smad2/3 dephosphorylation. Co-overexpression of SLC7A11-AS1 and activin A were found in pancreatic patients, and related with the extremely short survival periods. Knockdown of SLC7A11-AS1 and blockade of activin A signaling significantly reduced gemcitabine resistance in PDAC in vitro and in vivo.

Conclusions

SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation. Targeting both SLC7A11-AS1 and activin A may offer a potential therapeutic strategy for overcoming gemcitabine resistance in PDAC.