2. Academic Validation
  3. p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia

p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia

  • Exp Cell Res. 2025 Dec 19;455(2):114870. doi: 10.1016/j.yexcr.2025.114870.
Manish Bhat 1,  Mythreyi Narasimhan 2,  Ashutosh Shelar 3,  Raghavendra Patwardhan 4,  Santosh Kumar Sandur 5,  Rukmini Govekar 6
Affiliations

Affiliations

  • 1 Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, 410 210, India; Homi Bhabha National Institute, BARC Training School Complex, Mumbai, 400 094, India. Electronic address: [email protected].
  • 2 Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, 410 210, India; Homi Bhabha National Institute, BARC Training School Complex, Mumbai, 400 094, India. Electronic address: [email protected].
  • 3 Shimadzu Analytical (India) Pvt. Ltd., Mumbai, 400 059, India. Electronic address: [email protected].
  • 4 Bhabha Atomic Research Centre (BARC), Mumbai, 400 085, India; Homi Bhabha National Institute, BARC Training School Complex, Mumbai, 400 094, India. Electronic address: [email protected].
  • 5 Bhabha Atomic Research Centre (BARC), Mumbai, 400 085, India; Homi Bhabha National Institute, BARC Training School Complex, Mumbai, 400 094, India. Electronic address: [email protected].
  • 6 Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, 410 210, India; Homi Bhabha National Institute, BARC Training School Complex, Mumbai, 400 094, India. Electronic address: [email protected].
PMID: 41423144 DOI: 10.1016/j.yexcr.2025.114870
Abstract

Background: Metabolic reprogramming is a hallmark of Cancer and its role in tumour drug resistance is emerging. This study explored its role in resistance to tyrosine kinase inhibitors (TKIs) in the blast crisis (BC) phase of chronic myeloid leukemia (CML), which occurs despite inactivation of the oncogenic Bcr-Abl by TKIs. We previously reported that this Bcr-Abl-independent resistance is mimicked in TKI-resistant CML-BC cell line and is causally associated with p38MAPK, a known modulator of metabolism. Thus, we investigated whether p38MAPK-mediated metabolic rewiring caused resistance in CML-BC.

Methods: Imatinib sensitive and resistant CML-BC cell lines K562 and KU812 were analysed for metabolic proteins by Western blotting, metabolome by mass spectrometry, and Apoptosis, mitochondrial membrane potential (MMP), and Reactive Oxygen Species (ROS) by flow cytometry. Sequence of alterations was established by inhibition and knockdown studies.

Results: TKI-resistant cells exhibited enhanced glucose uptake, increased levels of GLUT1, glycolytic Enzymes, and those of pyruvate and ATP which reduced upon inhibition of GLUT1, indicative of enhanced glycolysis as contributor of energy. In contrast, the cells displayed reduced NADH/NAD ratio, MMP, mitochondrial ROS which resulted in reduction in apoptotic population. Inhibition studies revealed that suppression of hyperphosphorylated p38MAPK-mediated activation of Nrf2, caused reduced mitochondrial pyruvate carrier (MPC2) expression. MPC2 inhibition in sensitive cells recapitulated the resistant phenotype with reduced MMP and ROS levels.

Conclusion: p38MAPK-mediated suppression of Nrf2/MPC2 axis abrogates mitochondrial function and ROS-mediated cell death while enhanced glycolysis generates ATP to sustain growth. The resultant pro-survival conditions allow leukemic cell survival under drug pressure causing resistance.

Keywords

Chronic myeloid leukemia; Imatinib resistance; Metabolic reprogramming; Mitochondrial dysfunction; Nrf2/MPC2 axis; p38MAPK signalling.

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