Tyrosine Phosphorylation of Mitochondrial Creatine Kinase 1 Enhances a Druggable Tumor Energy Shuttle Pathway

Cell Metabolism
Kiran KurmiTaro Hitosugi

Abstract

How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2+ breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation. Inhibition of the phosphocreatine energy shuttle by MtCK1 knockdown or with the creatine analog cyclocreatine decreases proliferation of trastuzumab-sensitive and -resistant HER2+ cell lines in culture and in xenografts. Finally, we show that cyclocreatine in combination with the HER2 kinase inhibitor lapatinib reduces the growth of a trastuzumab-resistant HER2+ patient-derived xenograft. These findings suggest that activation of the phosphocreatine energy shuttle by MtCK1 Y153 phosphorylation creates a druggable metabolic vulnerability in cancer.

Citations

Jul 10, 2019·Journal of Dental Research·J LiC Fang
Jul 14, 2020·Frontiers in Physiology·Anna GumàAntonio Zorzano
Jun 5, 2020·Nature Reviews. Endocrinology·Lawrence Kazak, Paul Cohen
Jan 1, 2021·Molecular Cell·Alba LuengoMatthew G Vander Heiden
Apr 18, 2020·Trends in Cell Biology·Kiran Kurmi, Marcia C Haigis
Mar 4, 2021·Cell Metabolism·Marc L Reitman
Oct 13, 2021·Molecular Cancer Research : MCR·Yuan ZhangPetr Starostik

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.

Breast Tumorigenesis

Breast tumorigenesis involves the production or formation of tumor(s) in breast tissue. Discover the latest research on breast tumorigenesis here.