Cluster of Differentiation 166 (CD166) Regulated by Phosphatidylinositide 3-Kinase (PI3K)/AKT Signaling to Exert Its Anti-apoptotic Role via Yes-associated Protein (YAP) in Liver Cancer

Ma, Lifang; Wang, Jiayi; Lin, Jie; Pan, Qiuhui; Yu, Yongchun; Sun, Fenyong

doi:10.1074/jbc.m113.524819

Cited by 47 publications

(63 citation statements)

References 37 publications

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“…Notably, overexpression of Bcl-2 also diminishes death induced by expression of FOXO proteins (20). We previously reported that the anti-apoptotic function of CD166 is via enhancement of both expression and activity of oncoprotein, YAP (7). The degradation of YAP can be protected by TRIB2 (21)(22), a protein that is also capable of inhibiting and reducing nuclear FOXO proteins (23).…”

Section: Discussionmentioning

confidence: 99%

“…5F). These two types of proteins play opposing roles in the regulation of tumorigenesis in liver cancer (6,7,11,18,19). Nuclear localization of FOXO proteins induces expression of anti-carcinogenic genes (11), whereas CD166 facilitates translocation of FOXO proteins from the nucleus to the cytoplasm (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that the activation of anti-apoptotic canonical NF-κB signaling greatly induces CD166 expression in liver cancer cells after serum deprivation (6), suggesting its important roles in regulating apoptosis. Most recently, we revealed that CD166 can exert its anti-apoptotic role by enhancing YAP function, demonstrating that CD166 is an upstream regulator of YAP (7). However, overexpression of YAP cannot completely rescue the increased anti-carcinogenic effects evoked by knockdown of CD166 (7).…”

Section: Introductionmentioning

confidence: 96%

“…Most recently, we revealed that CD166 can exert its anti-apoptotic role by enhancing YAP function, demonstrating that CD166 is an upstream regulator of YAP (7). However, overexpression of YAP cannot completely rescue the increased anti-carcinogenic effects evoked by knockdown of CD166 (7). Thus, the downstream regulation of the CD166 pro-carcinogenic function needs to be further explored.…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported that silencing of CD166 can induce apoptosis (7). Notably, activation of FOXO proteins can also induce apoptosis (13).…”

Section: Cd166 Regulates Phosphorylation Of Foxo Proteinsmentioning

confidence: 99%

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CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

Wang

et al. 2014

Oncology Reports

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Abstract. Cluster of differentiation 166 (CD166) is a cell surface membrane protein, which is regarded as a valuable prognostic marker in several types of epithelial tumors. We previously reported that CD166 exerts its pro-carcinogenic role by enhancing YAP function in liver cancer cells. However, YAP cannot completely rescue the increased anti-carcinogenic effects by gene silencing of CD166, whose downstream effectors require further investigation. Here, we found that knockdown of CD166 inhibits phosphorylation of anti-carcinogenic FOXO proteins. Overexpression of CD166 led, not only to a faster protein degradation rate, but also a more accumulated ubiquitination of FOXO compared to the control. Moreover, overexpression of CD166 facilitated FOXO protein localization from the nuclear fraction to the cytosolic fraction, suggesting that CD166 modulates FOXO protein stability through alteration of their subcellular localization. In addition, simultaneous overexpression of CD166 partially reversed the evoked anti-carcinogenic effects by overexpression of FOXO both in vitro and in vivo. Furthermore, CD166 knockdown-induced anti-carcinogenic effects and dephosphorylation of FOXO proteins were rescued by overexpression of AKT. In liver cancer tissues, we also observed that higher expression levels of CD166, phospho-AKT, total AKT and phospho-FOXO were correlated with lower expression levels of total FOXO, suggesting that the upregulation of CD166 leads to the activation of AKT, which in turn facilitates phosphorylation and degradation of FOXO. Taken together, our data demonstrate that AKT is an inter-mediator between the upstream regulator, CD166, and downstream effector, FOXO, in liver cancer cells. Disrupting the relationship between CD166 and the AKT/FOXO axis may serve as a novel therapeutic target for liver cancer patients. IntroductionCluster of differentiation 166 (CD166) is a cell surface member of the immunoglobulin superfamily (1), which is overexpressed and regarded as a valuable prognostic marker of disease progression and poor survival in several types of epithelial tumors (2-4). Gene silencing of CD166 decreases the concentration of Bcl-2 and increases the level of apoptosis (PARP, active caspase-7) (5). We previously reported that the activation of anti-apoptotic canonical NF-κB signaling greatly induces CD166 expression in liver cancer cells after serum deprivation (6), suggesting its important roles in regulating apoptosis. Most recently, we revealed that CD166 can exert its anti-apoptotic role by enhancing YAP function, demonstrating that CD166 is an upstream regulator of YAP (7). However, overexpression of YAP cannot completely rescue the increased anti-carcinogenic effects evoked by knockdown of CD166 (7). Thus, the downstream regulation of the CD166 pro-carcinogenic function needs to be further explored.The forkhead box transcription factor superfamily consists of 19 subclasses of FOX genes, FOXA-FOXS (8). The FOX transcription factors that belong to the other (O) subfamily (FOXO) include four memb...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

“…We previously reported that silencing of CD166 can induce apoptosis (7). Notably, activation of FOXO proteins can also induce apoptosis (13).…”

Section: Cd166 Regulates Phosphorylation Of Foxo Proteinsmentioning

confidence: 99%

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CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

Wang

et al. 2014

Oncology Reports

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Dual in vitro invasion/migration suppressing and tamoxifen response modulating effects of a recombinant anti‐ALCAM scFv on breast cancer cells

Darvishi

Salehi

Boroumandieh

et al. 2020

Cell Biochemistry & Function

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It has been shown that overexpression of activated leukocyte cell adhesion molecule (ALCAM) is involved in development of resistance to tamoxifen therapy and promotion of cell invasion, migration and metastasis in ER+ breast cancer cells. Thus, we hypothesized that blockade of ALCAM interconnections with antibodies could be an effective approach for reversing mentioned negative events associated with ALCAM overexpression in breast cancer cells. Here, an anti‐ALCAM scFv was recombinantly expressed and used throughout study for examination of the putative anticancer effects of ALCAM blockade. The anti‐ALCAM scFv coding sequence was obtained from GenBank database and after addition of a 6× His‐tag moiety, signal peptide and flanking sequences, the whole construct was expressed in Escherichia coli. Tamoxifen resistant MCF7 cells were then pretreat for 24 hours with purified recombinant anti‐ALCAM scFv prior to administration of tamoxifen. In parallel, the cytotoxicity profile of anti‐ALCAM scFv and tamoxifen co‐treatments against tamoxifen resistant and sensitive MCF7 cell lines was also evaluated using CompuSyn software. The invasion/migration inhibitory effects of anti‐ALCAM scFv on MDA‐MB‐231 cells were also evaluated. Pretreatment with anti‐ALCAM scFv could successfully enhance anti‐proliferative effects of tamoxifen against resistant MCF‐7 cell lines. Furthermore, the combination of 19.2:1 of tamoxifen to anti‐ALCAM scFv demonstrated synergistic cell inhibitory effect against tamoxifen resistant MCF7 cell lines. Also, incubating MDA‐MB‐231 cell lines with anti‐ALCAM scFv resulted in a 30% and 25% reduction in number of invaded and migrated cells respectively. Overall, application of anti‐ALCAM scFv could significantly suppress cancer cells metastasis in vitro and modulate tamoxifen resistant ER+ MCF7 cell line's sensitivity to tamoxifen.Significance of the studyAcquisition of resistance to tamoxifen therapy is one of the major challenges associated with cancer chemotherapy, gradually turning a responsive tumour into a refractory more invasive one which ultimately ends in disease progression and relapse. Here, we reported expression of an anti‐ALCAM scFv, capable of increasing the sensitivity of tamoxifen resistant ER+ MCF‐7 cells to tamoxifen therapy following a 24‐hour pretreatment period. In addition, we demonstrated that the anti‐ALCAM scFv monotherapy was also capable of suppressing invasion and migration of MDA‐MB‐231 cells in Boyden chamber assays.

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Long Noncoding RNA lncARSR Promotes Doxorubicin Resistance in Hepatocellular Carcinoma via Modulating PTEN‐PI3K/Akt Pathway

Feng

et al. 2017

J of Cellular Biochemistry

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Hepatocellular carcinoma (HCC) is generally resistant to chemotherapy due to intrinsic or acquired drug resistances. Many molecules and signaling pathways are involved in chemo-resistance of HCC cells. However, the contribution of long noncoding RNA (lncRNA) to chemo-resistance of HCC cells is still largely unknown. In this study, we revealed the critical roles of long noncoding RNA lncARSR in chemo-resistance of HCC cells. lncARSR is upregulated in HCC, associated with large tumor size and advanced BCLC stage, and indicts poor prognosis. Functional assays showed that overexpression of lncARSR enhances doxorubicin resistance of HCC cells in vitro and in vivo. And while knockdown of lncARSR increases sensitivity of HCC cells to doxorubicin in vitro and in vivo. Mechanistically, we found that lncARSR physically associates with PTEN mRNA, promotes PTEN mRNA degradation, decreases PTEN expression, and activates PI3K/Akt pathway. PTEN is downregulated in HCC, and the expression of PTEN is negatively correlated with lncARSR in HCC tissues. Furthermore, the effects of lncARSR overexpression on doxorubicin resistance could be reversed by PI3K/Akt pathway inhibitor, and lncARSR knockdown-induced doxorubicin sensitivity could be reversed by PTEN depletion. Taken together, our results showed that upregulated lncARSR promotes doxorubicin resistance in HCC via modulating PTEN-PI3K/Akt pathway, and implied that lncARSR may serve as a promising prognostic biomarker and therapeutic target for HCC chemo-resistance. J. Cell. Biochem. 118: 4498-4507, 2017. © 2017 Wiley Periodicals, Inc.

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Cluster of Differentiation 166 (CD166) Regulated by Phosphatidylinositide 3-Kinase (PI3K)/AKT Signaling to Exert Its Anti-apoptotic Role via Yes-associated Protein (YAP) in Liver Cancer

Cited by 47 publications

References 37 publications

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT

Dual in vitro invasion/migration suppressing and tamoxifen response modulating effects of a recombinant anti‐ALCAM scFv on breast cancer cells

Long Noncoding RNA lncARSR Promotes Doxorubicin Resistance in Hepatocellular Carcinoma via Modulating PTEN‐PI3K/Akt Pathway

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