Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Nikita S. Sharma, Prisca Gnamlin, Brittany Durden, Vineet K. Gupta, Kousik Kesh, Vanessa T. Garrido, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee

Research output: Contribution to journalArticle

Abstract

Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence. This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a “fail-safe” mechanism to prevent expansion of malignant cells to prevent further injury. Upon removal of the “stress” conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-non-coding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse. In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors.

Original languageEnglish (US)
Article number68
JournalOncogenesis
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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