Alpha fetoprotein is a novel protein‐binding partner for caspase‐3 and blocks the apoptotic signaling pathway in human hepatoma cells

Abstract

Although there is increasing evidence that alpha fetoprotein (AFP) may function as regulatory factor in the growth of tumor cells, the precise mechanism is still unclear. In the current study, we investigated the role of the cytoplasmic AFP in caspase-3-mediated signaling of apoptosis. Our results showed that low doses of TNF-related apoptosis-inducing ligand (TRAIL) elevated the activity of caspase-8, but not caspase-3. Caspase-3 colocalized and interacted with AFP in the cytoplasm of Bel 7402 cells, and translocated into nuclei in association with the occurrence of apoptosis while cells were under cotreatment with all-trans retinoic acid (ATRA) or TRAIL. AFP was able to form complexes with caspase-3 and block onward transmission of signaling from caspase-8. Knockdown of AFP increased the sensitivity of Bel 7402 cells to TRAIL, and thereby, triggered caspase-3 signaling. No intermolecule interaction occurred between AFP and caspase-8, nor was caspase-8 activity altered after AFP knockdown, demonstrating the selectivity of AFP in interfering with the apoptotic signaling pathway. The effect of AFP on caspase-3 was further confirmed by transfection of the AFP gene into HLE cells (AFP negative). We conclude that ATRA or TRAIL resistance in AFP producing hepatoma is at least, in part, attributable to the high level of the cytoplasmic AFP. Therefore, it is possible that the combination of AFP gene silencing together with ATRA/TRAIL cotreatment will benefit the enhancement of the chemotherapeutic efficiency of these agents on tumors. ' 2009 UICC

Cryotherapy is associated with improved clinical outcomes of sorafenib for the treatment of advanced hepatocellular carcinoma

“…The precise mechanism by which AFP affects prognosis remains unclear. However, several studies have reported that AFP is a novel protein-binding partner for caspase-3, which blocks the apoptotic signaling pathway, and promotes the growth of human hepatoma cells as a co-repressor in retinoic acid (RA)-RA receptor signaling (40,41). Therefore, the low AFP level was independently associated with better OS.…”

Effects of AFP gene silencing on Survivin mRNA expression inhibition in HepG2 cells

“…AFP is widely used as a biomarker for HCC diagnosis, monitoring, and follow-up, but studies of its biological function have only recently increased. Numerous studies confirmed that AFP has complicated biological functions, such as promoting liver cancer cell proliferation, inhibition of apoptosis, and immune evasion (Li et al, 2009;Coumar et al, 2013).…”

“…Previous studies showed that AFP plays an important role in cell proliferation and apoptosis of HCC (Yang et al, 2008;Li et al, 2009). Survivin is a recently discovered member of the apoptosis inhibitor protein family that is expressed in a variety of tumors but remains silent in normally differentiated tissues.…”

Alpha-Fetoprotein (AFP) and Inflammation: Is AFP an Acute and/or Chronic Phase Reactant?

“…As mentioned above in inflammation during pregnancy, AFP has been reported to interact and bind to caspase-3,9 enzymes (cysteine proteases) which constitute key components of molecular complexes called inflammosomes [34,79]. These inflammation-induced organelles are multiprotein oligomer formations that enhance inflammatory processes leading to cell death [80].…”

“…The combination of elevated AFP together with elevated ICAM-1 levels were correlated with pre-term birth, intrauterine growth retardation (IUGR), and prematurity [32]. AFP is known to bind to caspases; such agents are activated to mediate proteolytic processing of proinflammatory cytokine IL-1β, levels of which are elevated in some forms of preterm birth and maternal metabolic disorders [33,34].…”