Endocrine Abstracts

Objective: Abnormal mitochondria are well known in oxyphilic thyroid tumors but recent data also confirm profound mitochondrial alterations in other thyroid carcinomas. These changes are linked to the aggressiveness of the tumors. Our group recently demonstrated in an in vivo model, that inhibition of phosphoinositide 3-kinase (PI3K) signalling suppressed the invasive and metastatic behaviour of thyroid cancer cells. Here, we evaluated whether a modulation of PI3K signalling changes mitochondrial mass and function.

Methods: We used follicular (FTC-133, WRO) and anaplastic (8505C) carcinoma cell lines to characterize mitochondrial mass and function both under baseline conditions and inhibition of PI3K signaling. Therefore, we transfected phosphatase and tensin homolog (PTEN) mutated FTC-133 cells with wild type PTEN or empty vector. We compared these chronic effects with an acute inhibition of PI3K signaling over 18 h using the pan-PI3K inhibitor GDC-0941 in all cell lines.

Results: Mitochondrial mass remained unchanged in all cell lines but active mitochondria were significantly decreased by acute PI3K inhibition. This effect was most pronounced in FTC-133 cells. It was accompanied by a significant shift in oxygen consumption (directly measured by Clarke electrode), a decrease in the production of reactive oxygen species (Dihydrorhodamine 123 and MitoSOX) and reduced protein carbonylation (OxyBlot). Evaluation of proteins involved in mitochondrial biogenesis (PGC1α) and mitochondrial autophagy (BNIP3 and Beclin1) indicate a shift in the balance of biogenesis and autophagy upon acute PI3K inhibition. Electron microscopy confirmed a major change in mitochondrial ultrastructure and an increased number of lysosomes/autophagosomes.

Summary: Our data demonstrate that changes in PI3K signaling alter mitochondrial function. These functional data suggest a major impact of the PI3K cascade on the reprogramming of mitochondria in cancer. These mitochondrial alterations may have important consequences to explain the aggressiveness of thyroid cancer subtypes with activated PI3K.