LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases

Zhang, Yanghe; Meng, Qingfei; Sun, Qianhui; Xu, Zhixiang; Zhou, Honglan; Wang, Yishu

doi:10.1016/j.molmet.2020.101131

Cited by 49 publications

(43 citation statements)

References 123 publications

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“…Liver kinase B1 (LKB1) is a serine/threonine kinase that is widely present in various tissues and cells and regulates cell proliferation, metabolism, polarity, and migration ( Zhang Y. et al, 2021 ). LKB1 mainly acts by phosphorylating and activating adenosine monophosphate-activated protein kinase (AMPK) ( Hollstein et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…LKB1 mainly acts by phosphorylating and activating adenosine monophosphate-activated protein kinase (AMPK) ( Hollstein et al, 2019 ). Through AMPK, LKB1 regulates lipid metabolism, glycolysis, and other metabolic pathways to maintain the phenotype and function of normal cells ( Zhang Y. et al, 2021 ; Molina et al, 2021 ). LKB1 is also a negative regulator of inflammatory response ( Wu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

et al. 2021

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Liver kinase B1 (LKB1) is known to shape the regulation of macrophage function by participating in multiple processes including cell metabolism, growth, and polarization. However, whether LKB1 also affects the functional plasticity of macrophages in atherosclerosis has not attracted much attention. Abnormal macrophage function is a pathophysiological hallmark of atherosclerosis, characterized by the formation of foam cells and the maintenance of vascular inflammation. Mounting evidence supports that LKB1 plays a vital role in the regulation of macrophage function in atherosclerosis, including affecting lipid metabolism reprogramming, inflammation, endoplasmic reticulum stress, and autophagy in macrophages. Thus, decreased expression of LKB1 in atherosclerosis aggravates vascular injury by inducing excessive lipid deposition in macrophages and the formation of foam cells. To systematically understand the role and potential mechanism of LKB1 in regulating macrophage functions in atherosclerosis, this review summarizes the relevant data in this regard, hoping to provide new ideas for the prevention and treatment of atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

et al. 2021

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“…A growing body of evidence is accumulating of increased TCA cycle activity, mitochondrial membrane potential, and mitochondrial respiration 49 , 50 , 51 in LKB1‐deficient cancer cells to support their proliferation and survival. 52 Borzi and colleagues proposed that even NSCLC showing low expression of wild‐type LKB1 could undergo this metabolic evolution and may accordingly be more sensitive to antimetabolic drugs. 53 We therefore interrogated the TCGA database to see if there was evidence to support this metabolic evolution model in larger NSCLC patient cohorts.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, we could monitor that the phosphorylation cascade downstream of AMPK is activated in EVT‐701‐treated H460‐LKB1 cells, as shown by an increased phosphorylation state of 4E‐BP1 on Serine 65, Raptor and Acetyl CoA carboxylase (ACC) within minutes after exposure to EVT‐701, whereas parental H460 couldn't (Figure 4C). A growing body of evidence is accumulating of increased TCA cycle activity, mitochondrial membrane potential, and mitochondrial respiration 49–51 in LKB1‐deficient cancer cells to support their proliferation and survival 52 . Borzi and colleagues proposed that even NSCLC showing low expression of wild‐type LKB1 could undergo this metabolic evolution and may accordingly be more sensitive to antimetabolic drugs 53 .…”

Section: Resultsmentioning

confidence: 99%

EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers

Yolba¹,

Visentin²,

Hervé³

et al. 2021

Pharmacology Res & Perspec

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Targeting the first protein complex of the mitochondrial electron transport chain (MC1) in cancer has become an attractive therapeutic approach in the recent years, given the metabolic vulnerabilities of cancer cells. The anticancer effect exerted by the pleiotropic drug metformin and the associated reduction in hypoxia‐inducible factor 1α (HIF‐1α) levels putatively mediated by MC1 inhibition led to the development of HIF‐1α inhibitors, such as BAY87‐2243, with a more specific MC1 targeting. However, the development of BAY87‐2243 was stopped early in phase 1 due to dose‐independent emesis and thus there is still no clinical proof of concept for the approach. Given the importance of mitochondrial metabolism during cancer progression, there is still a strong therapeutic need to develop specific and safe MC1 inhibitors. We recently reported the synthesis of compounds with a novel chemotype and potent action on HIF‐1α degradation and MC1 inhibition. We describe here the selectivity, safety profile and anti‐cancer activity in solid tumors of lead compound EVT‐701. In addition, using murine models of lung cancer and of Non‐Hodgkin's B cell lymphoma we demonstrated that EVT‐701 reduced tumor growth and lymph node invasion when used as a single agent therapy. LKB1 deficiency in lung cancer was identified as a potential indicator of accrued sensitivity to EVT‐701, allowing stratification and selection of patients in clinical trials. Altogether these results support further evaluation of EVT‐701 alone or in combination in preclinical models and eventually in patients.

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“…STK11/LKB1 is also involved in signaling pathways involved in the DNA damage response to sun ultraviolet radiation as a contributor to skin cancer and it has been connected to other non-PJS-related epithelial cancers (3,4). In addition, control of certain immune cells has been reported to be under the influence of the STK11/LKB1 gene (5).…”

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confidence: 99%

Peutz‑Jeghers syndrome: Skin manifestations and endocrine anomalies (Review)

et al. 2021

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Peutz-Jeghers syndrome (PJS), a rare autosomal dominant serine/threonine kinase 11 (STK11)/ liver kinase B1 (LKB1) gene-related genodermatosis, is characterized by oral hyperpigmentation (OHP); multiple gastro-intestinal mucosal benign hamartomatous polyps causing local bleeding, occlusion, intussusception, post-resection small bowel syndrome, associated increased risk of small intestinal cancer (incidence during the third decade); and 76% cumulative higher risk than the global population of developing non-gastrointestinal tumors (female predominance) including ovarian/testicular neoplasia, pancreatic and gynecologic (breast, uterus, ovarian) cancers. Suggestive PJS-associated OHP requires STK11 genetic testing. Abdominal pain in an OHP patient may be related to PJS-associated polyps. Other features include focal depigmentation followed by hyperpigmentation, and xeroderma pigmentosum-like lesions. The severity of the dermatological findings is correlated with gastrointestinal polyps. The STK11 gene is linked to reserve of primordial follicles, polycystic ovary syndrome, female fertility, and spermatogenesis. PJS is associated with 2 types of ovarian sex-cord stroma tumors (SCSTs): annular tubules (SCTATs) and pure Sertoli cell tumors. SCSTs accounts for 8% of ovarian cancer and SCTATs represents 2% of SCST, which may be associated with the overproduction of progesterone. PJS-SCTAT vs. non-PJS-SCTAT reveals bilateral/multifocal, small tumors with a benign behavior vs. a unique ovarian, large tumor with increased malignant/metastasis risk. Male precocious puberty is due to large cell calcifying Sertoli cell tumors (LCCSCTs). Notably, 30-40% of LCCSCTs are caused by PJS or Carney complex. PJS-LCCSCT is not aggressive, but it may be bilateral/multifocal, with the ultrasound hallmark being micro-calcifications. Testicular, intra-tubular large cell hyalinizing Sertoli cell tumor is the second testicle neoplasia in PJS. The skin and mucosal lesions are useful markers of PJS, assisting with the early identification of hamartomatouspolyps and initiation of serial surveillance of ovarian, or testicular neoplasia.

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LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases

Cited by 49 publications

References 123 publications

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers

Peutz‑Jeghers syndrome: Skin manifestations and endocrine anomalies (Review)

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