lncRNA-encoded pep-AP attenuates the pentose phosphate pathway and sensitizes colorectal cancer cells to Oxaliplatin

EMBO Rep. 2022 Jan 5;23(1):e53140. doi: 10.15252/embr.202153140. Epub 2021 Nov 15.

Abstract

Oxaliplatin (L-OHP) is a standard treatment for colorectal cancer (CRC), but chemoresistance is a considerable challenge. L-OHP shows dose-dependent toxicity, and potential approaches that sensitize cancer cells to L-OHP could reduce the dosage. With the development of translatomics, it was found that some lncRNAs encode short peptides. Here, we use ribosome footprint profiling combined with lncRNA-Seq to screen 12 lncRNAs with coding potential, of which lnc-AP encodes the short peptide pep-AP, for their role in L-OHP resistance. Co-IP and LC-MS/MS data show that the TALDO1 protein interacts with pep-AP and that pep-AP suppresses the expression of TALDO1. The pep-AP/TALDO1 pathway attenuates the pentose phosphate pathway (PPP), reducing NADPH/NADP+ and glutathione (GSH) levels and causing ROS accumulation and apoptosis, which sensitizes CRC cells to L-OHP in vitro and in vivo. pep-AP thus might become a potential anticancer peptide for future treatments of L-OHP-resistant CRC.

Keywords: ROS; lncRNA; oxaliplatin resistance; pentose phosphate pathway; peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Chromatography, Liquid
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Oxaliplatin / pharmacology
  • Pentose Phosphate Pathway
  • RNA, Long Noncoding* / genetics
  • Tandem Mass Spectrometry

Substances

  • Antineoplastic Agents
  • RNA, Long Noncoding
  • Oxaliplatin