Oncogenic Properties of a Spermatogenic Meiotic Variant of Fer Kinase Expressed in Somatic Cells

Abstract

The kinase Fer and its spermatogenic meiotic variant, FerT, are coexpressed in normal testes and cancerous tumors, but whether they exert related roles in spermatogenic or malignant cells has not been known. Here, we show that Fer and FerT reside in the mitochondria of spermatogenic cells and are harnessed to the reprogrammed mitochondria of colon carcinoma cells. Both kinases bound complex I of the mitochondrial electron transport chain (ETC) in spermatogenic and in colon carcinoma cells, and silencing of either Fer or FerT was sufficient to impair the activity of this complex. Directed mitochondrial accumulation of FerT in nonmalignant NIH3T3 cells increased their ETC complex I activity, ATP production, and survival, contingent upon stress conditions caused by nutrient and oxygen deprivation. Strikingly, directed mitochondrial accumulation of FerT endowed nonmalignant cells with tumor-forming ability. Thus, recruitment of a meiotic mitochondrial component to cancer cell mitochondria highlights a pivotal role for reprogrammed mitochondria in tumorigenesis. Cancer Res; 74(22);

A novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells

“…Although the “Warburg effect” is a hallmark of the reprogrammed metabolism of cancer cells, these cells remain dependent on the integrity and functionality of their mitochondria for ATP production and fatty acid synthesis, a requirement that becomes most profound upon transition of the malignant disease to a metastatic phase 5 . Thus, the mitochondrial machinery undergoes reprogramming during the development and progression of malignant disease, a change that is reflected in the altered activity of several key enzymes 6 , 7 .…”

“…A recently reported player in mitochondrial reprogramming in cancer cells is the intracellular tyrosine-kinase, Fer, and its sperm and cancer cell-specific truncated variant, FerT, which are harnessed to the reprogrammed mitochondria in colon carcinoma 8 cells 7 . Fer populates several subcellular compartments in malignant cells, including the cytoplasmic membrane, mitochondria, and cell nucleus 7 , 9 , 10 . In the mitochondria, Fer and FerT associate with complex I of the mitochondrial electron transport chain (ETC) of malignant but not of normal somatic cells, thereby supporting ATP production in nutrient-deprived cancer cells, in a kinase dependent manner 7 .…”

“…Fer populates several subcellular compartments in malignant cells, including the cytoplasmic membrane, mitochondria, and cell nucleus 7 , 9 , 10 . In the mitochondria, Fer and FerT associate with complex I of the mitochondrial electron transport chain (ETC) of malignant but not of normal somatic cells, thereby supporting ATP production in nutrient-deprived cancer cells, in a kinase dependent manner 7 . Furthermore, silencing of either Fer or FerT is sufficient to impair ETC complex I activity.…”

“…Concomitantly, directed mitochondrial accumulation of FerT in nonmalignant NIH3T3 cells increases their ETC complex I activity, ATP production, and survival, contingent upon stress conditions imposed by nutrient and oxygen deprivation. Notably, enforced mitochondrial expression of FerT endowed the nonmalignant cells with an ability to form tumors in vivo 7 . Thus, recruitment of the meiotic FerT to cancer cell mitochondria highlights the primary role of reprogrammed mitochondria in tumorigenesis.…”

Light and electron microscopic study of mature spermatozoa from White Pekin duck (Anas platyrhynchos): an ultrastructural and molecular analysis

“…ATP5A has been shown to be present in the neck of bull spermatozoa (Yaffe et al . ). Notably, Mitofusin2 and ATP5A are exclusively absent in neck mitochondrial region and present in head and tail (as well as tip) of duck spermatozoa.…”