Editors' ChoiceCancer

Mitochondria power drug-induced invasion

Sci. Signal.  21 Jul 2015:
Vol. 8, Issue 386, pp. ec197
DOI: 10.1126/scisignal.aad0377

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is an important target in cancer; however, resistance to drugs that target this pathway is common. Caino et al. investigated the contribution of mitochondria to the mechanisms of resistance to PI3K inhibitors. Exposure of glioblastoma (GBM) LN229 tumor cells to various PI3K inhibitors led to adaptive response involving increased activity and abundance of proteins involved in the PI3K pathway. GBM LN229 tumor cells grown on Matrigel-coated Transwell inserts or as three-dimensional (3D) spheroids showed increased invasion after individual exposure to structurally diverse PI3K antagonists. Single-cell stroboscopic measurements, which track and quantify movement in images, revealed that PI3K antagonists stimulated lamellipodia dynamics and increased the duration of individual membrane ruffles. Immunofluorescence microscopy analysis of GBM LN229 tumor cells exposed to antagonists to PI3K revealed that mitochondria were elongated and colocalized with phosphorylated focal adhesion kinase (FAK) in the cortical cytoskeleton, suggesting that mitochondria contributed to motility induced by PI3K inhibition. PI3K antagonists increased the abundance of mitochondrial superoxide dismutase in PC3 cells, a prostate cancer cell line, and this response was abolished by the reactive oxygen species (ROS) scavenger mitoTEMPO, indicating a role for ROS produced by mitochondria in cell motility. Exposure of primary GBM neurospheres to a mitochondrial inhibitor, Gamitinib, or to inhibitors of mitochondrial respiration, abolished the increase in tumor cell invasiveness and inhibited mitochondrial movement to the cortical cytoskeleton in response to PI3K antagonists. Individual knockdown of the kinases Akt1, Akt2, mTOR, or FAK in PC3 cells prevented PI3K inhibitor-induced mitochondrial redistribution to the cortical cytoskeleton and reduced the invasive phenotype. Thus, mitochondria relocation to the periphery may contribute to resistance to PI3K therapy by providing energy for cell migration.

M. C. Caino, J. C. Ghosh, Y. C. Chae, V. Vaira, D. B. Rivadeneira, A. Faversani, P. Rampini, A. V. Kossenkov, K. M. Aird, R. Zhang, M. R. Webster, A. T. Weeraratna, S. Bosari, L. R. Languino, D. C. Altieri, PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proc. Natl. Acad. Sci. U.S.A. 112, 8638–8643 (2015). [PubMed]