Phosphomimetic Mutants of Pigment Epithelium-Derived Factor with Enhanced Anti-Choroidal Melanoma Cell Activity In Vitro and In Vivo

Feng, Yongdong; Bao, Wenjing; Luo, Yanli; Tian, Ling; Chen, Xiafang; Yi, Miaoying; Xiong, Hui; Huang, Qian

doi:10.1167/iovs.12-10326

Cited by 10 publications

(4 citation statements)

References 39 publications

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“…More recently, the same group reported the molecular mechanism by which phosphomimetic PEDF exerts more-profound effects at the cellular level by inducing JNK-dependent apoptosis and p38-mediated migration arrest 77 . More recently, Feng and co-workers 126 demonstrated that the triple phospho mimetic EEE-PEDF significantly reduced the growth and metastasis of choroidal melanoma xenografts in nude mice, and this effect was associated with inhibiting VEGF and NF-κB expression. Is has been proposed that EEE-PEDF has an increased negative charge compared with the wild-type protein.…”

Section: Regulation Of Pedfmentioning

confidence: 97%

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

2013

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The potent actions of pigment epithelium-derived factor (PEDF) on tumour-associated cells, and its extracellular localization and secretion, stimulated research on this multifunctional serpin. Such studies have identified several PEDF receptors and downstream signalling pathways. Known cellular PEDF responses have expanded from the initial discovery that PEDF induces retinoblastoma cell differentiation to its anti-angiogenic, antitumorigenic and antimetastatic properties. Although the diversity of PEDF activities seems to be complex, they are consistent with the varied mechanisms that regulate this multimodal factor. If PEDF is to be used for cancer management, a deeper appreciation of its many functions and mechanisms of action is needed.

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Section: Regulation Of Pedfmentioning

confidence: 97%

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

2013

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“…Choroidal melanoma is the most frequently occurring primary intraocular malignant tumor and is always accompanied by metastasis and poor survival [ 1 ]. In addition, the cancer is insensitive to many commonly used chemotherapeutic drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Choroidal melanoma is the most common primary malignant tumor of the eye, accounting for approximately 70% of all primary intraocular eye tumors [ 1 ], and the second most common type of malignant melanoma affecting the body. Approximately 50% of choroidal melanomas metastasize within 15 years of the primary diagnosis [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells

et al. 2017

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Choroidal melanoma is the most common primary malignant intraocular tumor, and very few effective therapies are available to treat it. Our study aimed to understand whether pemetrexed plus cisplatin exerts a beneficial synergistic effect in human choroidal melanoma cells and to delineate the underlying molecular mechanism. To accomplish these aims, we treated choroidal melanoma cells with pemetrexed and cisplatin and assessed cell survival with SRB and MTT assays. Proteins were detected using western blotting analysis. NOXA and CHOP were knocked down with siRNA. We found that pemetrexed or cisplatin alone inhibited survival and induced apoptosis in human choroidal melanoma cells. Furthermore, the expression levels of c-FLIP, an anti-apoptotic protein in the extrinsic apoptosis pathway, and Mcl-1, an anti-apoptotic protein in the intrinsic apoptosis pathway, were decreased by pemetrexed or cisplatin respectively, while the expression of a pro-apoptotic protein in the intrinsic apoptosis pathway, NOXA, was up-regulated. Moreover, pemetrexed or cisplatin alone increased the protein expression of the endoplasmic reticulum stress markers IRE1α, Bip and CHOP. Silencing CHOP expression reduced NOXA expression. These findings suggest that the pemetrexed or cisplatin induced intrinsic apoptosis via activation of the ER stress response. Importantly, combining the two compounds more strongly induced apoptosis. Following the cotreatment, CHOP and NOXA expression increased, while c-FLIP and Mcl-1 expression decreased, and these effects were more pronounced than when using either compound alone. This result suggests that pemetrexed and cisplatin synergistically activate ER stress response-induced apoptosis in choroidal melanoma cells. To summarize, the c-FLIP and NOXA/Mcl-1 axis participated in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells. Intrinsic apoptosis was induced via activation of the ER stress response. Our study provides important mechanistic insights into potential cancer treatment with pemetrexed plus cisplatin and enriches our understanding of human choroidal melanoma.

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“…Melanoma cells prevent the decrease in PEDF in fibroblasts, leading to the development of a cancer-promoting phenotype in cancer-associated fibroblasts [90]. An intriguing discovery was made, in that PEDF phosphomimetic mutants were shown to significantly decrease the development of tumours and curb the spread of tumours in melanoma xenografts within nude mouse models compared to the regular PEDF [91]. Thus, PEDF phosphomimetic mutants may offer more effective results in preventing and impeding metastasis, though this needs more testing [92].…”

Section: Pedf Molecular Pathways In Cancer and Role In Cancer Prognos...mentioning

confidence: 99%

The Various Roles of PEDF in Cancer

Elmi,

Dass,

Dass

2024

Cancers

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Pigment epithelium-derived factor (PEDF) is a natural immunomodulator, anti-inflammatory, anti-angiogenic, anti-tumour growth and anti-metastasis factor, which can enhance tumour response to PEDF but can also conversely have pro-cancerous effects. Inflammation is a major cause of cancer, and it has been proven that PEDF has anti-inflammatory properties. PEDF’s functional activity can be investigated through measuring metastatic and metabolic biomarkers that will be discussed in this review.

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Phosphomimetic Mutants of Pigment Epithelium-Derived Factor with Enhanced Anti-Choroidal Melanoma Cell Activity In Vitro and In Vivo

Cited by 10 publications

References 39 publications

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells

The Various Roles of PEDF in Cancer

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