ERK2-Pyruvate Kinase Axis Permits Phorbol 12-Myristate 13-Acetate-induced Megakaryocyte Differentiation in K562 Cells.
Metabolic changes that contribute to differentiation are not well understood. Overwhelming evidence shows the critical role of glycolytic enzyme pyruvate kinase (PK) in directing metabolism of proliferating cells. However, its role in metabolism of differentiating cells is unclear. Here we studied the role of PK in phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic differentiation in human leukemia K562 cells. We observed that PMA treatment decreased cancer-type anabolic metabolism but increased ATP production, along with up-regulated expression of two PK isoforms (PKM2 and PKR) in an ERK2-dependent manner. Interestingly, silencing of PK (PKM2 and PKR) inhibited PMA-induced megakaryocytic differentiation, as revealed by decreased expression of megakaryocytic differentiation marker CD61 and cell cycle behavior. Further, PMA-induced ATP production reduced greatly upon PK silencing, suggesting that PK is required for ATP synthesis. In addition to metabolic effects, PMA treatment also translocated PKM2, but not PKR, into nucleus. ERK1/2 knockdowns independently and together suggested the role of ERK2 in the up-regulation of both the isoforms of PK, proposing a role of ERK2-PK isoform axis in differentiation. Collectively, our findings unravel ERK2 guided PK-dependent metabolic changes during PMA induction, which are important in megakaryocytic differentiation.
From the National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
Noor
N
Chaman
From the National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
Mohammad Askandar
MA
Iqbal
From the National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
Farid Ahmad
FA
Siddiqui
From the National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
Prakasam
P
Gopinath
From the National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India bamezai@hotmail.com bamezai@mail.jnu.ac.in.
Rameshwar N K
RN
Bamezai
D002273:Carcinogens / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008533:Megakaryocytes / Q000166:cytology / Q000201:enzymology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D002273:Carcinogens; C061248:ITGB3 protein, human; D039661:Integrin beta3; D011770:Pyruvate Kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D013755:Tetradecanoylphorbol Acetate
K562; cancer biology; chronic myelogenous leukemia (CML); differentiation; megakaryocytes; metabolism; pyruvate kinase; tumor metabolism