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

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.

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

“…However, cancer cells rely on glycolysis as their preferred energy source using a phenomenon called the Warburg effect, named after the German biochemist, Otto Warburg, who discovered that cancer cells used a different metabolic pathway than normal cells [ 75 ]. Multiple peer-reviewed publications from our group corroborate these observations as well [ 6 , 7 , 12 ]. Interestingly, the metabolic phenotype of CSCs appears to vary across different tumor types and tumor microenvironments.…”

“…This is manifested in the CSCs by enhanced resistance to therapy along with high metastatic potential. A recently published study from our group shows that under nutritional deprivation or hypoxia or due to chemotherapy treatment, the CD133 + CSC population markedly upregulates the long-noncoding RNA GAS5 [ 12 ]. This promotes quiescence in this population of CSCs, thereby helping these cells to survive during these stressful conditions.…”

“…Additionally, CD133 + CSCs also have their metabolites routed through the biosynthetic pathways. Thus, the upregulation of GAS5 and suppression of proliferation, along with key metabolites in the biosynthetic pathways, puts these cells in a uniquely advantageous position in which they can regain their aggressive proliferative potential as soon as these adverse conditions recede [ 12 ].…”

Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV

“…Previous studies in cancer have suggested that GAS5 puts a "brake" on cell proliferation, thereby acting as a potential tumor suppressor in various cancers (46). Also, overexpression of GAS5 has been shown to increase apoptosis and reduce cell cycle progression in T cell lines and PBMCs (47).…”

Stem cell quiescence and its clinical relevance

“…Knockdown of DANCR transcript reduced self-renewal capacity and quiescence of LSCs in a AML murine model[ 137 ]. The lncRNA growth arrest-specific 5 was highly expressed in the CD133 + pancreatic CSC population and was found to suppress proliferation by inhibiting glucocorticoid receptor-mediated cell cycle regulation[ 138 ].…”