Mevalonate pathway blockage enhances the efficacy of mTOR inhibitors with the activation of retinoblastoma protein in renal cell carcinoma

Hagiwara, Nobuhisa; Watanabe, Motoki; Iizuka-Ohashi, Mahiro; Yokota, Isao; Toriyama, Seijiro; Sukeno, Mamiko; Tomosugi, Mitsuhiro; Sowa, Yoshihiro; Hongo, Fumiya; Mikami, Kōichi; Soh, Jintetsu; Fujito, Akira; Miyashita, Hiroaki; Morioka, Yukako; Miki, Tsuneharu; Ukimura, Osamu

doi:10.1016/j.canlet.2018.05.025

Cited by 19 publications

(10 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…And it can inhibits mTOR, blocking a critical downstream effector of growth factor signaling. Although everolimus is safe and well tolerated, emerging drug resistance has been found 87. Since inhibition of mTOR could induce autophagy, activation of autophagy may be a key mechanism for everolimus resistance.…”

Section: Application Of Autophagy-related Drugs In Renal Carcinomamentioning

confidence: 99%

Role of Autophagy in Renal Cancer

Cao¹,

Bai²

2019

J. Cancer

View full text Add to dashboard Cite

Autophagy is a highly conserved catabolic process with critical functions in maintenance of cellular homeostasis under normal growth conditions and in preservation of cell viability under stress. The role of autophagy in cancer is dual-sided. Autophagy-deficient cells are often more tumorigenic than their wild type counterparts in association with DNA damage accumulation, oxidative stress. At the same time, autophagy is a major cell survival mechanism. In recent years, it has been well demonstrated that autophagy may have relation with renal cell carcinoma (RCC). This review focuses on the research progress in relation between autophagy and RCC and the pharmacologic manipulation of autophagy for RCC treatment.

show abstract

Section: Application Of Autophagy-related Drugs In Renal Carcinomamentioning

confidence: 99%

Role of Autophagy in Renal Cancer

Cao¹,

Bai²

2019

J. Cancer

View full text Add to dashboard Cite

show abstract

“…mTOR inhibitor induced a robust activation of retinoblastoma protein via inhibits KRAS or Rac1 protein prenylation, and statins treatment also enhanced the efficacy of an mTOR inhibitor in RCC xenograft models[132] …”

mentioning

confidence: 98%

Statins: a repurposed drug to fight cancer

Jiang

et al. 2021

J Exp Clin Cancer Res

219

142

View full text Add to dashboard Cite

As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins.

show abstract

“…Inhibiting autophagy sensitizes resistant cancer cells to chemotherapeutic drugs [ 37 ], which suggests that inhibiting autophagy may overcome drug resistance. Although everolimus (an mTOR inhibitor) is considered a second-line treatment for RCC after sunitinib treatment failure, increasing drug resistance is a problem [ 38 ]. Since inhibiting mTOR induces autophagy, activating autophagy may be a key mechanism underlying resistance to everolimus [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma

Kang

Lee

et al. 2020

Cells

View full text Add to dashboard Cite

More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog (MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation rate of less than 4%. MDM2 is master regulator of apoptosis in cancer cells, which is triggered through proteasomal degradation of wild-type p53. Recently, we found that p53 protein levels in RCC are regulated by autophagic degradation. Transglutaminase 2 (TGase 2) was responsible for p53 degradation through this pathway. Knocking down TGase 2 increased p53-mediated apoptosis in RCC. Therefore, we asked whether depleting p53 from RCC cells occurs via MDM2-mediated proteasomal degradation or via TGase 2-mediated autophagic degradation. In vitro gene knockdown experiments revealed that stability of p53 in RCC was inversely related to levels of both MDM2 and TGase 2 protein. Therefore, we examined the therapeutic efficacy of inhibitors of TGase 2 and MDM2 in an in vivo model of RCC. The results showed that inhibiting TGase 2 but not MDM2 had efficient anticancer effects.

show abstract

Mevalonate pathway blockage enhances the efficacy of mTOR inhibitors with the activation of retinoblastoma protein in renal cell carcinoma

Cited by 19 publications

References 47 publications

Role of Autophagy in Renal Cancer

Role of Autophagy in Renal Cancer

Statins: a repurposed drug to fight cancer

Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma

Contact Info

Product

Resources

About