Apoptosis inhibitor 5 increases metastasis via Erk-mediated MMP expression

Song, Kwon Ho; Kim, Seok Ho; Noh, Kyung Hee; Bae, Hyun Cheol; Kim, Jin Hee; Lee, Hyo‐Jung; Song, Jinhoi; Kang, Tae Heung; Kim, Dong Wan; Oh, Se Jin; Jeon, Ju Hong; Kim, Tae Woo

doi:10.5483/bmbrep.2015.48.6.139

Cited by 22 publications

(18 citation statements)

References 13 publications

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“…AAC-11 (antiapoptosis clone 11), also called Api5 or FIF, is an antiapoptotic protein whose expression prevents apoptosis following growth factor deprivation (1). Many cancer cells exhibit elevated levels of AAC-11, which were found to correlate with poor prognosis in patients with non-small cell lung cancer and cervical cancer and contribute to tumor invasion and metastases (2)(3)(4)(5)(6)(7)(8)(9)(10). Interestingly, AAC-11 appears to be involved in anticancer drugs-induced apoptosis of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

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A Cell-Penetrating Peptide Targeting AAC-11 Specifically Induces Cancer Cells Death

et al. 2016

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AAC-11 is an antiapoptotic protein that is upregulated in most cancer cells. Increased expression of AAC-11 confers a survival advantage when cancer cells are challenged with various stresses and contributes to tumor invasion and metastases, whereas its deregulation reduces resistance to chemotherapeutic drugs. The antiapoptotic effect of AAC-11 may be clinically relevant as its expression correlates with poor prognosis in several human cancers. Thus, inactivation of AAC-11 might constitute an attractive approach for developing cancer therapeutics. We have developed an AAC-11-derived cell-penetrating peptide, herein named RT53, mimicking in part the heptad leucine repeat region of AAC-11, which functions as a protein-protein interaction module, and that can prevent AAC-11 antiapoptotic properties. In this study, we investigated the anticancer effects of RT53. Our results indicate that RT53 selectively kills cancer cells while sparing normal cells. RT53 selectively inserts into the membranes of cancer cells, where it adopts a punctate distribution and induces membranolysis and release of danger-associated molecular pattern molecules. Systemic administration of RT53 inhibited the growth of preexisting BRAF wild-type and V600E mutant melanoma xenograft tumors through induction of apoptosis and necrosis. Toxicological studies revealed that repetitive injections of RT53 did not produce significant toxicity. Finally, RT53-killed B16F10 cells induced tumor growth inhibition in immunocompetent mice following a rechallenge with live cancer cells of the same type. Collectively, our data demonstrate that RT53 possesses tumor-inhibitory activity with no toxicity in mice, suggesting its potential as a therapeutic agent for the treatment of melanoma and probably other cancers. Cancer Res; 76(18); 5479-90. ©2016 AACR.

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Section: Introductionmentioning

confidence: 99%

“…AAC-11 interacts with several apoptosis-related proteins and this complex-forming ability, probably favored by its elongated 3D structure (14), appears to be essential for AAC-11 to fulfill its antiapoptotic functions (1,9,11,15,16). Therefore, inhibitors of AAC-11 protein-protein interactions could prove to be of clinical benefit.…”

Section: Introductionmentioning

confidence: 99%

A Cell-Penetrating Peptide Targeting AAC-11 Specifically Induces Cancer Cells Death

et al. 2016

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“…Additionally, Api5 was necessary for the migration of the MCF7 cells induced by E2. Recently, a report indicated that Api5 is involved in the metastatic process by increasing MMP expression [ 29 ]. In vivo , xenografted MCF7 cells depleted for Api5 in nude mice were unable to form actively growing tumors compared to the control and displayed significantly a reduced proliferation index.…”

Section: Discussionmentioning

confidence: 99%

Api5 a new cofactor of estrogen receptor alpha involved in breast cancer outcome

et al. 2017

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Api5 (Apoptosis inhibitor 5) is an anti-apoptotic factor that confers resistance to genotoxic stress in human cancer. Api5 is also expressed in endothelial cells and participates to the Estrogen Receptor α (ERα) signaling to promote cell migration. In this study, we found an over expression of Api5 in human breast cancer. Given that we show that high expression of Api5 in breast cancer patients is associated with shorter recurrence free survival, we investigated the relationship between ERα and Api5 at the molecular level. We found that Api5 Nuclear Receptor box (NR box) drives a direct interaction with the C domain of ERα. Furthermore, Api5 participates to gene transcription activation of ERα target genes upon estrogen treatment. Besides, Api5 expression favors tumorigenicity and migration and is necessary for tumor growth in vivo in mice xenografted model of breast cancer cell line. These finding suggest that Api5 is a new cofactor of ERα that functionally participates to the tumorigenic phenotype of breast cancer cells. In ERα breast cancer patients, Api5 overexpression is associated with poor survival, and may be used as a predictive marker of breast cancer recurrence free survival.

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“…Zhu's study identified a positive feedback loop between TOPK and ERK2 [ 30 ]. Accumulating evidence indicates that the ERK pathway can promote the migration and invasion of cancer cells and is closely associated with metastasis [ 46 - 49 ]. Our study demonstrates that when TOPK is highly expressed in CTCs, phospho-ERK is also highly expressed (Figure 3B ), and when TOPK is knocked down, the expression of phospho-ERK was also downregulated (Figure 4E ).…”

Section: Discussionmentioning

confidence: 99%

TOPK is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer

et al. 2015

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Circulating tumor cells (CTCs) are important for metastasis in prostate cancer. T-LAK cell-originated protein kinase (TOPK) is highly expressed in cancer cells. Herein, we established a xenograft animal model, isolated and cultured the CTCs, and found CTCs have significantly greater migratory capacity than parental cells. TOPK is more highly expressed in the CTCs than in parental cells and is also highly expressed in the metastatic nodules caused by CTCs in mice. Knocking down TOPK decreased the migration of CTCs both in vitro and in vivo. TOPK was modulated by the PI3K/PTEN and ERK pathways during the metastasis of prostate cancer. High levels of TOPK in the tumors of patients were correlated with advanced stages of prostate cancer, especially for high-risk patients of Gleason score≥8, PSA>20ng/ml. In summary, TOPK was speculated to be one of a potential marker and therapeutic target in advanced prostate cancer.

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Apoptosis inhibitor 5 increases metastasis via Erk-mediated MMP expression

Cited by 22 publications

References 13 publications

A Cell-Penetrating Peptide Targeting AAC-11 Specifically Induces Cancer Cells Death

A Cell-Penetrating Peptide Targeting AAC-11 Specifically Induces Cancer Cells Death

Api5 a new cofactor of estrogen receptor alpha involved in breast cancer outcome

TOPK is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer

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