Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects

Jiao, Zhihua; Cai, Huaqing; Lan, Yu; Sirka, Orit Katarina; Padmanaban, Veena; Ewald, Andrew J.; Devreotes, Peter N.

doi:10.1073/pnas.1917938117

Cited by 41 publications

(42 citation statements)

References 43 publications

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“…"class effect," where statins deplete GGPP and hinder the prenylation of multiple proteins important for cell survival [52]. Further investigation is required to elucidate the importance of protein prenylation in t(4;14)-positive MM, and delineate the relationship between GGPP metabolism and the ISR.…”

Section: Discussionmentioning

confidence: 99%

“…Hundreds of proteins are predicted to be prenylated in mammalian cells [ 40 , 51 ], and therefore it is not surprising that attempts to rescue statin-induced apoptosis with select individual prenylated proteins have largely failed [ 10 ]. More recent evidence supports a “class effect,” where statins deplete GGPP and hinder the prenylation of multiple proteins important for cell survival [ 52 ]. Further investigation is required to elucidate the importance of protein prenylation in t (4;14)-positive MM, and delineate the relationship between GGPP metabolism and the ISR.…”

Section: Discussionmentioning

confidence: 99%

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The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma

Longo

Смирнов

et al. 2020

Leukemia

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Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients with t(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that t(4;14)-positive cells are highly dependent on the mevalonate (MVA) pathway for survival. Moreover, we showed that this metabolic vulnerability is immediately actionable, as inhibiting the MVA pathway with a statin preferentially induced apoptosis in t(4;14)-positive cells. In response to statin treatment, t(4;14)-positive cells activated the integrated stress response (ISR), which was augmented by co-treatment with bortezomib, a proteasome inhibitor. We identified that t(4;14)positive cells depend on the MVA pathway for the synthesis of geranylgeranyl pyrophosphate (GGPP), as exogenous GGPP fully rescued statin-induced ISR activation and apoptosis. Inhibiting protein geranylgeranylation similarly induced the ISR in t(4;14)-positive cells, suggesting that this subtype of MM depends on GGPP, at least in part, for protein geranylgeranylation. Notably, fluvastatin treatment synergized with bortezomib to induce apoptosis in t(4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate the t(4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment of t(4;14)-positive disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma

Longo

Смирнов

et al. 2020

Leukemia

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“…[55] These distinct cellular uptake mechanisms offer therapeutic benefits for exosome-based cancer therapies. For example, since oncogenic KRAS signaling promotes exosome micropinocytosis, [56] exosomes harboring KRAS siRNA can induce selective effects against KRAS mutant tumors. [23] In addition, the fusion of exosomes with cell membranes facilitates the transfer of therapeutic exosomal cargos into the cytoplasm of target cells while escaping lysosomal degradation.…”

Section: Cellular Uptake Mechanismmentioning

confidence: 99%

Emerging Prospects of Exosomes for Cancer Treatment: From Conventional Therapy to Immunotherapy

et al. 2020

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remains unclear how and why cancer occurs and progresses. Using an evolutionary approach, the concept of a complex adaptive system (CAS) was developed to describe the behaviors of cancer tumorigenesis, [2] which may suggest a frameshift away from the limitations of current approaches that mainly address the importance of alteration in specific target molecules in cancer cells. This change in perspectives toward tumors, not simply as a disease to be cured but also as CAS, is expected to be the cornerstone of the paradigm shift toward innovative cancer therapies. [3] The human immune system can also be viewed as a CAS and therefore expected to initiate self-defense mechanisms against cancer in a complex adaptive manner as long as it recognizes the cancer cells as the non-self-signals. Consequently, the key to controlling cancer could lie in understanding how to manipulate the immune system and strengthen its defenses against cancer. The concept of facilitating the immune system to fight against cancer was first suggested in the late 1800s by Dr. Wiliam Coley, who was the first to observe anti-tumor effects after intratumoral injection of microbe-derived toxins. [4] Since then, the field of cancer immunotherapy research has flourished, resulting in clinical achievements such as immune checkpoint blockades and chimeric antigen receptor T cell (CAR-T) therapy. [5] However, immune suppression resistance mechanisms have simultaneously been identified that have impeded favorable response to cancer immunotherapy. [6,7] Exosome-based cancer therapies have emerged as a potential option for overcoming these limitations to the effects of current cancer therapies due to their pathophysiological efficacy against tumors. [8] Exosomes are secreted externally by cells and are found ubiquitously in blood, urine, saliva, cerebrospinal fluid, pleural fluid, and breast milk. [9,10] The distinction between different types of extracellular vesicles (EVs) is unclear; however, they are conventionally classified as either ectosomes (microvesicles or microparticles) or exosomes. [11] While ectosomes are formed by the outward budding of the plasma membrane, exosomes are formed from multivesicular bodies (MVB) containing intraluminal vesicles via inward budding of the late endosome, which later fuses to the membrane. The formed vesicles are then secreted via a process known as exocytosis (Figure 1). The two types of vesicle also differ in diameter, Exosomes are a class of extracellular vesicles of around 100 nm in diameter that are secreted by most cells and contain various bioactive molecules reflecting their cellular origin and mediate intercellular communication. Studies of these exosomal features in tumor pathogenesis have led to the development of therapeutic and diagnostic approaches using exosomes for cancer therapy. Exosomes have many advantages for conveying therapeutic agents such as small interfering RNAs, microRNAs, membrane-associated proteins, and chemotherapeutic compounds; thus, they are considered a prime candidate as a deliv...

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“… 27 In addition, Jiao et al found that administration of pitavastatin to human MCF10A, one of the non-malignant breast epithelial cells, resulted in depletion of GGPP in the mevalonate pathway and starvation of amino acids, eventually leading to cell death. 28 …”

Section: Molecular Biological Mechanisms For the Anticancer Effects Of Pitavastatinmentioning

confidence: 99%

The Anti-Cancer Effect of Pitavastatin May Be a Drug-Specific Effect: Subgroup Analysis of the TOHO-LIP Study

Nagayama¹,

Saiki²,

Shirai³

2021

VHRM

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The significance of statin treatment for the reduction of cardiovascular (CV) disease has been reported, whereas other reports have also described anti-cancer properties associated with the class effect of statins. However, the differences in anti-cancer effect of various types of statins have rarely been examined. Pitavastatin is a statin with a different chemical structure and pharmacokinetics from other statins, and the mechanism of the specific anti-cancer effect of pitavastatin has been reported in in vivo therapeutic models. We previously revealed that pitavastatin therapy was superior to atorvastatin therapy in the prevention of CV events, despite similar LDL-cholesterol-lowering effect in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP). Furthermore, in subgroup analysis of the TOHO-LIP study, cumulative 240-week incidence of new cancer cases tended to be lower in the pitavastatin group compared to the atorvastatin group [0.32% (1/312) vs 1.94% (6/310), log-rank P=0.051]. This finding might reveal the superiority of pitavastatin to prevent carcinogenesis. The molecular mechanism by which pitavastatin suppresses the incidence of any-organ cancer is gradually elucidated, and new combination of cancer treatments with pitavastatin will be developed in the future to further enhance the anti-cancer activity and reduce the side effects.

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Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects

Cited by 41 publications

References 43 publications

The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma

The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma

Emerging Prospects of Exosomes for Cancer Treatment: From Conventional Therapy to Immunotherapy

The Anti-Cancer Effect of Pitavastatin May Be a Drug-Specific Effect: Subgroup Analysis of the TOHO-LIP Study

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