The early signals generated following cross‐linking of Fas/APO‐1, a transmembrane receptor whose engagement by ligand results in apoptosis induction, were investigated in human HuT78 lymphoma cells. Fas/APO‐1 cross‐linking by mAbs resulted in membrane sphingomyelin hydrolysis and ceramide generation by the action of both neutral and acidic sphingomyelinases. Activation of a phosphatidylcholine‐specific phospholipase C (PC‐PLC) was also detected which appeared to be a requirement for subsequent acidic sphingomyelinase (aSMase) activation, since PC‐PLC inhibitor D609 blocked Fas/APO‐1‐induced aSMase activation, but not Fas/APO‐1‐induced neutral sphingomyelinase (nSMase) activation. Fas/APO‐1 cross‐linking resulted also in ERK‐2 activation and in phospholipase A2 (PLA2) induction, independently of the PC‐PLC/aSMase pathway. Evidence for the existence of a pathway directly involved in apoptosis was obtained by selecting HuT78 mutant clones spontaneously expressing a newly identified death domain‐defective Fas/APO‐1 splice isoform which blocks Fas/APO‐1 apoptotic signalling in a dominant negative fashion. Fas/APO‐1 cross‐linking in these clones fails to activate PC‐PLC and aSMase, while nSMase, ERK‐2 and PLA2 activates are induced. These results strongly suggest that a PC‐PLC/aSMase pathway contributes directly to the propagation of Fas/APO‐1‐generated apoptotic signal in lymphoid cells.

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PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.