PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells
William J Israelsen1, Talya L Dayton, Shawn M Davidson
1Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.
Insights
Pyruvate kinase M2 (PKM2) is not essential for tumor growth. Its absence accelerated tumor formation, indicating PKM2 regulates distinct metabolic needs of proliferating versus nonproliferating cancer cells.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Pyruvate kinase M2 (PKM2) is implicated in cancer metabolism.
- PKM2 regulates anabolic pathways crucial for tumor growth.
Purpose of the Study:
- To investigate the necessity of PKM2 for tumor formation and growth.
- To elucidate the role of PKM2 in cancer cell proliferation and metabolism.
Main Methods:
- Generated mice with a conditional allele to abolish PKM2 expression.
- Utilized a Brca1-loss-driven mouse model for breast cancer.
- Analyzed PKM2 and PKM1 expression in proliferating and nonproliferating tumor cells.
Main Results:
- PKM2 deletion accelerated mammary tumor formation.
- PKM2-null tumors showed heterogeneous PKM1 expression.
- Proliferating cells lacked detectable pyruvate kinase; nonproliferating cells expressed PKM1.
Conclusions:
- PKM2 is not required for tumor cell proliferation.
- PKM2 activity regulation supports metabolic heterogeneity in tumors.
- Findings are consistent with variable PKM2 expression and mutations in human tumors.
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