Targeting PP2A with lomitapide suppresses colorectal tumorigenesis through the activation of AMPK/Beclin1-mediated autophagy

Zuo, Qian; Liao, Long; Yao, Ziting; Liu, Yaping; Wang, Ding-Kang; Li, Shujun; Yin, Xinhua; He, Qing‐Yu; Xu, Wenwen

doi:10.1016/j.canlet.2021.09.010

Cited by 24 publications

(29 citation statements)

References 56 publications

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“…6E ), which validates the lomitapide-mediated activation of autophagy system. During the preparation of this manuscript, Zuo et al reported that lomitapide plays a role in the control of cancer cell death [ 41 ], which is consistent with our findings. These authors reported that lomitapide suppresses the dephosphorylation of AMPK by directly inhibiting protein phosphatase 2 A (PP2A).…”

Section: Resultssupporting

confidence: 91%

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Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

et al. 2022

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Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.

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Section: Resultssupporting

confidence: 91%

“…These findings support the therapeutic advantages of lomitapide over other mTOR inhibitors. In light of our results and Zuo et al’s report [ 41 ], we believe that lomitapide’s superior anticancer activity can be achieved by targeting multiple autophagy signaling hubs including mTORC1 and PP2A.…”

Section: Discussionsupporting

confidence: 78%

Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

et al. 2022

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“…LiP‐SMap is a reliable technique to identify target proteins of drugs. [ 16 ] In this study, RanBP3 was identified as a direct target of NU2058. RanBP3 is a RanGTP‐binding protein that has been reported to enhance nuclear export of active β ‐catenin, independent of its role as a CRM1‐associated nuclear export cofactor.…”

Section: Discussionmentioning

confidence: 98%

Blockade of Nuclear β‐Catenin Signaling via Direct Targeting of RanBP3 with NU2058 Induces Cell Senescence to Suppress Colorectal Tumorigenesis

et al. 2022

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Colorectal cancer (CRC) is one of the most common malignant tumors in the world, with high prevalence and low 5-year survival. Most of the CRC patients show excessive activation of the Wnt/𝜷-catenin pathway which is a vital target for CRC treatment. Based on multiple CRC cell lines with different nuclear expression of 𝜷-catenin, NU2058 is identified from a small molecule library consisting of 280 bioactive compounds and found to selectively inhibit the proliferation of CRC cells with nuclear 𝜷-catenin activation in vitro and in vivo. The translational significance of NU2058 alone or in combination with chemotherapeutic drugs oxaliplatin and irinotecan (SN38) in CRC is demonstrated in orthotopic tumor model and patient-derived xenograft models. By integrating limited proteolysis-small molecule mapping (LiP-SMap) and mass spectrometry (MS), Ran-binding protein 3 (RanBP3) is identified as the direct target of NU2058. The results show that RanBP3 is a tumor suppressor in CRC and is associated with patient survival. Mechanistically, NU2058 increases the interaction of RanBP3 and 𝜷-catenin to promote nuclear export of 𝜷-catenin, which further inhibits transcription of c-Myc and cyclin D1 to induce cell senescence. Collectively, NU2058 may serve as a promising therapeutic agent for CRC patients with selective disruption of pathologic Wnt/𝜷-catenin signaling.

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“…In addition, activated AMPK also phosphorylates downstream tuberous sclerosis complex 1 and 2 (TSC1/2) to enhance inhibition of Rheb, thereby inhibiting mTOR and inducing autophagy ( 19 ). In HCT116 and HT29 human CRC cells, knockdown of AMPK restricted tumor autophagy-dependent cell death, leading to tumor progression ( 20 ) ( Figure 1 ).…”

Section: Crucial Pathways For Autophagy Regulation In Crcmentioning

confidence: 99%

“…In addition to natural products, there are several repositioning small-molecule compounds that contribute to CRC therapy via modulating autophagy. For instance, lomitapide, a clinical drug approved by the Food and Drug Administration (FDA) for the treatment of hypercholesterolemia, is recently reported to upregulate AMPK phosphorylation and promote the formation of BECN1-VPS34-ATG14 complex, thereby inducing autophagy in HCT116 and HT29 human CRC cells, which significantly inhibits tumor proliferation in vitro and in vivo ( 20 ). Similarly, flubendazole, an anthelmintic drug approved by FDA, downregulates STAT3 phosphorylation levels, mTOR and p62, and upregulates Beclin 1 and LC3-I/II in HCT116, RKO and SW480 human CRC cells, which promoting the initiation of autophagy to prevent tumor progression without substantially affecting normal cell proliferation ( 38 ).…”

Section: Therapeutic Strategies Targeting Autophagy For Crc Therapymentioning

confidence: 99%

Deconvoluting the complexity of autophagy in colorectal cancer: From crucial pathways to targeted therapies

Qiang

Liu²,

Wang³

et al. 2022

Front. Oncol.

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Colorectal cancer (CRC) is a common gastrointestinal tumor with a high degree of malignancy, and most clinical cases are diagnosed at an advanced stage, which has unfortunately missed an opportunity for surgery; therefore, elucidation of the crucial pathways of CRC development and discovery of targeted therapeutic strategies should be anticipated. Autophagy, which is an evolutionarily highly conserved catabolic process, may promote tumorigenesis and development of CRC. On the contrary, autophagy can trigger programmed cell death to inhibit CRC progression. Correspondingly, several targeted therapeutic strategies have been reported in CRC, including small-molecule compounds, polypeptides, non-coding RNAs, photodynamic, and adjuvant therapies. Thus, in this review, we focus on summarizing the crucial pathways of autophagy in CRC, and further discuss the current therapeutic strategies targeting autophagy. Together, these findings may shed light on the key regulatory mechanisms of autophagy and provide more promising therapeutic approaches for the future CRC therapies.

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Targeting PP2A with lomitapide suppresses colorectal tumorigenesis through the activation of AMPK/Beclin1-mediated autophagy

Cited by 24 publications

References 56 publications

Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

Blockade of Nuclear β‐Catenin Signaling via Direct Targeting of RanBP3 with NU2058 Induces Cell Senescence to Suppress Colorectal Tumorigenesis

Deconvoluting the complexity of autophagy in colorectal cancer: From crucial pathways to targeted therapies

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