TY - JOUR
T1 - PFKFB3 works on the FAK-STAT3-SOX2 axis to regulate the stemness in MPM
AU - Sarkar Bhattacharya, Sayantani
AU - Thirusangu, Prabhu
AU - Jin, Ling
AU - Staub, Julie
AU - Shridhar, Viji
AU - Molina, Julian R.
N1 - Funding Information:
This work is supported (in part) by the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (JM and VS) and a generous gift from Samuel and Ilda Conde to JM—Mayo Clinic, Rochester.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/10/19
Y1 - 2022/10/19
N2 - Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm and often acquires chemoresistance by increasing stemness in tumour tissue, thereby generating cancer stem cells (CSCs). CSCs escape treatment by deploying metabolic pathways to trigger dormancy or proliferation, also gaining the ability to exit and re-enter the cell cycle to hide their cellular identity. Methods: We employed various cellular and biochemical assays to identify the role of the glycolytic enzyme PFKFB3, by knocking it down and pharmacologically inhibiting it with PFK158, to determine its anticancer effects in vitro and in vivo by targeting the CSC population in MPM. Results: Here, we have identified PFKFB3 as a strategic player to target the CSC population in MPM and demonstrated that both pharmacologic (PFK158) and genetic inhibition of PFKFB3 destroy the FAK-Stat3-SOX2 nexus resulting in a decline in conspicuous stem cell markers viz. ALDH, CD133, CD44, SOX2. Inhibition of PFKFB3 accumulates p21 and p27 in the nucleus by decreasing SKP2. Lastly, PFK158 diminishes tumour-initiating cells (TICs) mediated MPM xenograft in vivo. Conclusions: This study confers a comprehensive and mechanistic function of PFKFB3 in CSC maintenance that may foster exceptional opportunities for targeted small molecule blockade of the TICs in MPM.
AB - Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm and often acquires chemoresistance by increasing stemness in tumour tissue, thereby generating cancer stem cells (CSCs). CSCs escape treatment by deploying metabolic pathways to trigger dormancy or proliferation, also gaining the ability to exit and re-enter the cell cycle to hide their cellular identity. Methods: We employed various cellular and biochemical assays to identify the role of the glycolytic enzyme PFKFB3, by knocking it down and pharmacologically inhibiting it with PFK158, to determine its anticancer effects in vitro and in vivo by targeting the CSC population in MPM. Results: Here, we have identified PFKFB3 as a strategic player to target the CSC population in MPM and demonstrated that both pharmacologic (PFK158) and genetic inhibition of PFKFB3 destroy the FAK-Stat3-SOX2 nexus resulting in a decline in conspicuous stem cell markers viz. ALDH, CD133, CD44, SOX2. Inhibition of PFKFB3 accumulates p21 and p27 in the nucleus by decreasing SKP2. Lastly, PFK158 diminishes tumour-initiating cells (TICs) mediated MPM xenograft in vivo. Conclusions: This study confers a comprehensive and mechanistic function of PFKFB3 in CSC maintenance that may foster exceptional opportunities for targeted small molecule blockade of the TICs in MPM.
UR - http://www.scopus.com/inward/record.url?scp=85133620767&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133620767&partnerID=8YFLogxK
U2 - 10.1038/s41416-022-01867-7
DO - 10.1038/s41416-022-01867-7
M3 - Article
C2 - 35794237
AN - SCOPUS:85133620767
SN - 0007-0920
VL - 127
SP - 1352
EP - 1364
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 7
ER -