Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf‐1 and Caspase‐9 apoptosome expression

Abstract

Autocrine motility factor (AMF) is a cytokine that regulates locomotion and metastasis of tumor cells. It is well known that expression levels of AMF secretion and its receptor (AMF R) are closely related to tumor malignancy and rheumatoid arthritis. We have established that AMF signaling induced anti-apoptotic activity and that human fibrosarcoma HT-1080 line that secreted high levels of AMF were resistant to drug-induced apoptosis. These cells did not express the apoptotic protease activating factor-1 (Apaf-1) and Caspase-9 genes that encode for the proteins that form the "apoptosome" complex. The disappearance of the Apaf-1 and Caspase-9 gene was recovered by a cellular signaling inhibitor of protein kinase C, phosphatidylinositol 3-phosphate kinase and mitogen-activated protein kinase of the in vitro apoptosome Cancer is a disease in which down-regulation of apoptosis often occurs, and this often appears to compromise chemotherapy using anti-cancer drugs. It is well known that abnormal regulation of many mitochondria-related factors, such as Bcl-2, cytochrome c, Bax, Bik, Mn SOD, APAF-1 and Caspase-9, is observed in cancer cells. For example, the lack or loss of apoptotic proteinase activating factor-1 (Apaf-1) was observed in metastatic melanomas, which can contend with chemotherapy and are unable to execute the typical apoptotic programme in response to p53 activation. 1 Sensitivity to apoptosis induced by UV light dependent on its Apaf-1 deficiency level, 2 and over-expression of Apaf-1 induced etoposide-or paclitaxel-sensitive apoptosis, 3,4 have been reported in human leukemia cell lines. However, over-expression or experimental transduction of Apaf-1 and caspase-9 genes promoted the apoptotic sensitivities to radiation or the chemotherapeutic index of glioma cells. [5][6][7] Thus, the expression levels of Apaf-1 and caspase-9 in tumor cells seem to be important factors in determining the malignancy of the cells, and control of their expression may produce a therapeutic effect in clinical cancer treatments such as radiation and anti-cancer drugs. 8,9 Apaf-1 and caspase-9 are the core proteins of the "apoptosome" complex, which has an essential role in inducing mitochondrial programmed cell death. 10 It is necessary for the activation of pro-caspase-9 that cytochrome c and dATP interact with Apaf-1 as cofactors, and then the activated caspase-9 turns on the effector caspase-3 that then kills the cell by proteolysis. 11 Therefore, the apoptosome is a key molecular event of programmed cell death in several diseases that express an unusual apoptotic regulation, such as cancer. The function of the apoptosome is controlled by multiple molecules, transforming growth factor-beta up regulation via cytochrome c release, 12 heat shock protein 70 and 90 downregulation by binding to Apaf-1 and the formation of a cytosolic complex. [13][14][15] However, it is poorly understood at the molecular level why Apaf-1 and caspase-9 are decreased in malignant cells and how they regulate the function of the apoptosome. Ke...

Autocrine motility factor/phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium release

“…30 AMF/PGI activation of pAkt has previously been shown to mediate AMF/PGI anti-apoptosis function. 15,18,25 Indeed, the ability of AMF/PGI to protect against etoposide-induced cell death that is not associated with induction of ER stress, confirms that the anti-apoptotic activity of AMF/PGI is not limited to the ER stress response. Etoposide-induced apoptosis is prevented by inhibition of the PI3K-Akt pathway 31 consistent with previous reports that AMF/PGI protects against serum starvation-induced cell death in NIH-3T3 fibroblasts by PI3K/Akt signaling.…”

“…15,25 The AMF/PGI receptor, gp78/AMFR, is an ER membraneanchored ubiquitin ligase (E3) that is a key component of the ERAD machinery involved in ubiquitination of ER proteins, 26,27 thereby suggesting a possible role in protecting cells against ER stress. In this study, we demonstrate that AMF/PGI protects against ER stress and associated apoptosis by the intermediary of its receptor, gp78/AMFR.…”

“…34,35 AMF/PGI protects against chemotherapeutic agents in vitro as well as in implanted tumors wherein it protects against paclitaxelmediated cell death. 25,36 AMF/PGI interaction with gp78/ AMFR may therefore contribute to tumor cell survival and resistance to chemotherapy by limiting the ER stress response of tumor cells growing in the harsh conditions of the tumor microenvironment.…”

Phosphoglucose Isomerase/Autocrine Motility Factor Promotes Melanoma Cell Migration through ERK Activation Dependent on Autocrine Production of Interleukin-8

“…rAMF Induces Cell Migration but Not Cell Proliferation in Two Melanoma Cell Lines (SBcl-2 and 1205Lu)-AMF is critical for the migration, invasion, metastasis, and anti-apoptotic effects of malignant tumor cells, and its multiple roles in tumor progression may be mediated by certain downstream pathways and effectors (2,5,6,8,(33)(34)(35). A previous study reported that melanoma cells secrete and respond to AMF in an autocrine manner with increased motility (2).…”

A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow

“…In the formation of metastases, tumor cells first migrate from the primary tumor site to vessels as single cells or masses before entering the circulation which transports them to distant parts of the body. Primary liver cancers are usually treated with pro-apoptotic anti-cancer drugs (Kinoshita et al 2000;Haga et al 2003;Sekharam et al 2003). However, by the time metastases occur, tumor cells have already acquired a resistance to these drugs.…”