Abstract
An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions. Notably, some DGK isoforms, such as DGKα, have been reported to possess promising therapeutic potential in cancer therapy. However, further studies are needed in order to better comprehend their involvement in cancer. In this review, we highlight that DGKs are an essential component of the PI cycle that localize within several subcellular compartments, including the nucleus and plasma membrane, together with their PI substrates and that they are involved in mediating major cancer cell mechanisms such as growth and metastasis. DGKs control cancer cell survival, proliferation, and angiogenesis by regulating Akt/mTOR and MAPK/ERK pathways. In addition, some DGKs control cancer cell migration by regulating the activities of the Rho GTPases Rac1 and RhoA.
Highlights
Phosphoinositides (PIs) represent a tiny component of the total phospholipid content in eukaryotic cell membranes, but they regulate numerous cellular activities such as cell adhesion [1], migration [2], apoptosis [3], vesicular trafficking [4], and post-translational modifications [5]
DAG and phosphatidic acid (PA) are involved in the regulation of several critical enzymes, including mammalian target of rapamycin [10], phosphatidylinositol-4-phosphate 5-kinase (PIP5K), the Ras GTPase-activating protein (GAP), rapidly accelerated fibrosarcoma-1 (Raf-1) kinase, protein kinases C (PKCs), mammalian uncoordinated 13 (Unc-13), Chimaerins, and rat sarcoma virus guanyl nucleotide-releasing protein (RasGRP), which are involved in cell proliferation and migration [11,12]
This review aims to provide up-to-date knowledge of the regulatory roles played by Diacylglycerol kinases (DGKs) in cancer cell survival and metastasis, while highlighting the downstream regulation of DGKs, the role of their cellular localization and summing up current knowledge on targeting DGKs in cancer therapies
Summary
Phosphoinositides (PIs) represent a tiny component of the total phospholipid content in eukaryotic cell membranes, but they regulate numerous cellular activities such as cell adhesion [1], migration [2], apoptosis [3], vesicular trafficking [4], and post-translational modifications [5]. These processes are consistent with cancer-associated cellular mechanisms. In 3D colon and breast cancer models, DGKα was reported to promote cell survival by regulating Src [28]. This review aims to provide up-to-date knowledge of the regulatory roles played by DGKs in cancer cell survival and metastasis, while highlighting the downstream regulation of DGKs, the role of their cellular localization and summing up current knowledge on targeting DGKs in cancer therapies
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