Adeno-associated virus mediated gene transfer of Shepherdin inhibits gallbladder carcinoma growth in vitro and in vivo

Zhu, Aiguo; Ren, Yu; Wang, Ning; Jin, Qiu-Yue; Zhang, Dongchang; Yang, Guangxiao; Wang, Quanying

doi:10.1016/j.gene.2015.06.080

Cited by 7 publications

(3 citation statements)

References 33 publications

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“…Shepherdin, a survivin 79 KHSSGCAFL 87 (minimum: 79 KHSSG 83 ) peptidomimetic agent, interrupts heat shock protein (Hsp) 90 interactions with survivin [4,5]. Alternatively, shepherdin was incorporated into cancer cells using adenovirus-mediated expression systems, thus demonstrating a proof of principle for use of agents that disrupt survivin-Hsp90 binding as an anticancer agent [6,7]. Since the peptidemimetic approach has the inherent weaknesses of stability and delivery issues, a small molecule inhibitor, AICAR (Figure 1a), was identified and found to disrupt multiple Hsp90 client proteins including survivin [8].…”

Section: Inhibitors That Disrupt Survivin Interactions With Its Partnmentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

195

171

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Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

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Section: Inhibitors That Disrupt Survivin Interactions With Its Partnmentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

195

171

View full text Add to dashboard Cite

show abstract

“…Shepherdin is a potent anticancer peptidomimetic antagonist of the survivin-Hsp90 complex, which can occupy the ATP-pocket of Hsp90 [16]. It was reported that shepherdin exerted significant pro-apoptotic effects mainly by promoting rapid degradation of survivin in multiple cancer cell lines and xenograft mouse models [16,39,40]. However, since Hsp90 also chaperones some tumor suppressive proteins such as interferon regulatory factor 1, LATS1 and LATS2 kinases, shepherdin's inhibition on Hsp90 might deregulate tumor suppressor pathways, which might be one of the reasons why shepherdin failed in clinical application [41].…”

Section: Discussionmentioning

confidence: 99%

Sur-X, a novel peptide, kills colorectal cancer cells by targeting survivin-XIAP complex

Fang

Che

et al. 2020

J Exp Clin Cancer Res

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Background Survivin and XIAP are two important members of the inhibitor of apoptosis protein family and have been considered as potential targets for cancer treatment due to their overexpression in large variety of cancers including colorectal cancer. It has been reported that survivin and XIAP can synergistically inhibit apoptosis by forming survivin-XIAP complex. In this study, we aimed to design a peptide that targets the survivin-XIAP complex and elucidate its anticancer mechanisms in colorectal cancer cells. Methods We designed and synthetized Sur-X, the peptide targeting survivin-XIAP complex. The anticancer effects of Sur-X were evaluated both in vitro and in vivo. The underlying molecular mechanisms were also investigated. Results Sur-X exhibited potent inhibitory effects on four colorectal cancer cell lines HCT116, HCT15, RKO and HT29, but not on human peritoneal mesothelial cell line HMrSV5. Mechanistically, Sur-X induced Caspase 9-dependent intrinsic apoptosis in colorectal cancer cells by disrupting the survivin-XIAP complex and subsequently destabilizing survivin and XIAP. Interestingly, we found that Sur-X can also promote necroptosis. It was demonstrated that Sur-X destroyed the interaction between XIAP and TAB1 in the XIAP-TAB1-TAK1 complex, leading to the instability of TAK1, an endogenous necroptosis inhibitor. Subsequently, the accelerated degradation of TAK1 attenuated its inhibition on necroptosis in colorectal cancer cells. Moreover, knockdown of TAK1 restored the sensitivity of TAB1-overexpressing colorectal cancer cells to Sur-X-induced necroptosis. The in vivo pro-apoptotic effect of Sur-X was confirmed by the enhanced TUNEL staining and the decreased expression of survivin and XIAP in tumor tissues from xenograft mouse models. In addition, extensive necrosis and weaker MLKL expression in xenografts provided evidence for the in vivo pro-necroptotic effect of Sur-X. Conclusions Peptide Sur-X exhibits strong pro-apoptotic and pro-necroptotic effects in colorectal cancer cells and has a high clinical translation potential in the treatment of colorectal cancer.

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“…Shepherdin is a cell-penetrating peptide mimetic able of accumulating in mitochondria and inhibit both TRAP1 and HSP90 [ 97 , 98 ]. To achieve prolonged Shepherdin production and release, researchers tested delivery of Shepherdin using adeno-associated virus (AAV) vectors [ 107 , 108 ].…”

Section: Trap1 Inhibitors and Neuroprotectionmentioning

confidence: 99%

TRAP1 in Oxidative Stress and Neurodegeneration

et al. 2021

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Tumor necrosis factor receptor-associated protein 1 (TRAP1), also known as heat shock protein 75 (HSP75), is a member of the heat shock protein 90 (HSP90) chaperone family that resides mainly in the mitochondria. As a mitochondrial molecular chaperone, TRAP1 supports protein folding and contributes to the maintenance of mitochondrial integrity even under cellular stress. TRAP1 is a cellular regulator of mitochondrial bioenergetics, redox homeostasis, oxidative stress-induced cell death, apoptosis, and unfolded protein response (UPR) in the endoplasmic reticulum (ER). TRAP1 has attracted increasing interest as a therapeutical target, with a special focus on the design of TRAP1 specific inhibitors. Although TRAP1 was extensively studied in the oncology field, its role in central nervous system cells, under physiological and pathological conditions, remains largely unknown. In this review, we will start by summarizing the biology of TRAP1, including its structure and related pathways. Thereafter, we will continue by debating the role of TRAP1 in the maintenance of redox homeostasis and protection against oxidative stress and apoptosis. The role of TRAP1 in neurodegenerative disorders will also be discussed. Finally, we will review the potential of TRAP1 inhibitors as neuroprotective drugs.

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Adeno-associated virus mediated gene transfer of Shepherdin inhibits gallbladder carcinoma growth in vitro and in vivo

Cited by 7 publications

References 33 publications

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Sur-X, a novel peptide, kills colorectal cancer cells by targeting survivin-XIAP complex

TRAP1 in Oxidative Stress and Neurodegeneration

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