Abstract
BackgroundLow nutrient environment is a major obstacle to solid tumor growth. However, many tumors have developed adaptive mechanisms to circumvent the requirement for exogenous growth factors.MethodsHere we used siRNA interference or plasmid transfection techniques to knockdown or enhance CD317 expression respectively, in mammalian cancer cells, and subjected these CD317-manipulated cells to serum deprivation to study the role of CD317 on stress-induced apoptosis and the underlying mechanism.ResultsWe report that CD317, an innate immune gene overexpressed in human cancers, protected cancer cells against serum deprivation-induced apoptosis. In tumor cells, loss of CD317 markedly enhanced their susceptibility to serum deprivation-induced apoptosis with no effect on autophagy or caspase activation, indicating an autophagy- and caspase-independent mechanism of CD317 function. Importantly, CD317 knockdown in serum-deprived tumor cells impaired mitochondria function and subsequently promoted apoptosis-inducing factor (AIF) release and nuclear translocation but had little effect on mitochondrial and cytoplasmic distributions of cytochrome C, a pro-apoptotic factor released from mitochondria that initiates caspase processing in response to death stimuli. Furthermore, overexpression of CD317 in HEK293T cells inhibits serum deprivation-induced apoptosis as well as the release and nuclear accumulation of AIF.ConclusionOur data suggest that CD317 functions as an anti-apoptotic factor through the mitochondria-AIF axis in malnourished condition and may serve as a potential drug target for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0391-2) contains supplementary material, which is available to authorized users.
Highlights
Low nutrient environment is a major obstacle to solid tumor growth
Considering that tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that can induce apoptosis in a wide range of cancers, and the translation of TRAIL into the clinic has been confounded by TRAIL-resistant cancer cell populations [19], we investigated whether CD317 involves in TRAIL-resistant mechanisms
In order to further confirm our observation in a broad spectrum of cancer calls, we examined the other four cell lines in the same experimental condition
Summary
Many tumors have developed adaptive mechanisms to circumvent the requirement for exogenous growth factors. Many tumors have developed adaptive mechanisms to circumvent this requirement for exogenous growth factors [1]. CD317 ( referred as tetherin, BST2, or HM1.24 antigen) is a type II transmembrane glycoprotein with an atypical membrane topology [4] It consists of an N-terminal transmembrane domain, extracellular coiled-coiled domain, and a C-terminal GPI anchor [4]. CD317 inhibits the release of many enveloped viruses from the surface of infected cells. These include all retroviruses tested as well as members from seven other families, such as Hepadnaviridae (Hepatitis B virus), Flaviviridae (Hepatitis C virus), Filoviridae (Ebola and Marburg viruses), Arenaviridae (Lassa fever virus), Herpesviridase (Kaposi’s sarcoma-associated herpesvirus), Paramyxoviridae (Sendai virus and Nipah virus), and Rabdoviridae
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