STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.
Molecular cancer
Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.
10.1186/s12943-023-01825-8
LKB1-dependent signaling pathways.
Alessi Dario R,Sakamoto Kei,Bayascas Jose R
Annual review of biochemistry
This review focuses on remarkable recent findings concerning the mechanism by which the LKB1 protein kinase that is mutated in Peutz-Jeghers cancer syndrome operates as a tumor suppressor. We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25). The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels. Genetic and biochemical findings indicate that LKB1 exerts its effects by phosphorylating and activating 14 protein kinases, all related to the AMP-activated protein kinase. The work described in this review shows how a study of an obscure cancer syndrome can uncover new and important regulatory pathways, relevant to the understanding of multiple human diseases.
10.1146/annurev.biochem.75.103004.142702
LKB1 regulated pathways in lung cancer invasion and metastasis.
Marcus Adam I,Zhou Wei
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Metastasis is characterized by the ability of cancer cells to invade into adjacent tissue, intravasate into blood or lymphatic vessels, and extravasate into a distant tissue. Metastatic disease is primarily responsible for the low 5-year survival rate of non-small cell lung cancer (NSCLC), and therefore, an understanding of the molecular mechanisms that regulate NSCLC metastasis is clearly warranted. The serine/threonine kinase and tumor suppressor LKB1 is mutated in 30% of NSCLC tumors, and recent evidence points to a prominent role in NSCLC metastasis. This review summarizes LKB1-dependent invasion pathways where compromised LKB1 function could promote NSCLC metastasis.
10.1097/JTO.0b013e3181fbc28a
LKB1 signaling and patient survival outcomes in hepatocellular carcinoma.
Pharmacological research
The liver is a major organ that is involved in essential biological functions such as digestion, nutrient storage, and detoxification. Furthermore, it is one of the most metabolically active organs with active roles in regulating carbohydrate, protein, and lipid metabolism. Hepatocellular carcinoma is a cancer of the liver that is associated in settings of chronic inflammation such as viral hepatitis, repeated toxin exposure, and fatty liver disease. Furthermore, liver cancer is the most common cause of death associated with cirrhosis and is the 3rd leading cause of global cancer deaths. LKB1 signaling has been demonstrated to play a role in regulating cellular metabolism under normal and nutrient deficient conditions. Furthermore, LKB1 signaling has been found to be involved in many cancers with most reports identifying LKB1 to have a tumor suppressive role. In this review, we use the KMPlotter database to correlate RNA levels of LKB1 signaling genes and hepatocellular carcinoma patient survival outcomes with the hopes of identifying potential biomarkers clinical usage. Based on our results STRADß, CAB39L, AMPKα, MARK2, SIK1, SIK2, BRSK1, BRSK2, and SNRK expression has a statistically significant impact on patient survival.
10.1016/j.phrs.2023.106757
Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells (Review).
Li Nianshuang,Huang Deqiang,Lu Nonghua,Luo Lingyu
Oncology reports
Liver kinase B1 (LKB1), also known as serine/threo-nine kinase 11 (STK11), is a tumor suppressor that is inactivated in Peutz-Jeghers familial cancer syndrome. LKB1 phosphorylates and activates AMP-activated protein kinase (AMPK), which negatively regulates cancer cell proliferation and metabolism. However, recent evidence demonstrates that the LKB1/AMPK pathway is involved in the process of tumor invasion and migration, which is an important hallmark of carcinoma progression to higher pathological grades of malignancy. This review focuses on the function of the LKB1/AMPK pathway in the invasion and migration of cancer cells and provides an overview of therapeutic strategies aimed at this pathway in malignant tumors.
10.3892/or.2015.4288
LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer.
Bonanno Laura,Zulato Elisabetta,Pavan Alberto,Attili Ilaria,Pasello Giulia,Conte PierFranco,Indraccolo Stefano
International journal of molecular sciences
Liver kinase B1 () is a tumor suppressor gene whose inactivation is frequent in different tumor types, especially in lung adenocarcinoma (about 30% of cases). LKB1 has an essential role in the control of cellular redox homeostasis by regulating ROS production and detoxification. Loss of LKB1 makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy. LKB1 loss triggers complex changes in tumor microenvironment, supporting a role in the regulation of angiogenesis and suggesting a potential role in the response to anti-angiogenic treatment. On the other hand, LKB1 deficiency can promote an immunosuppressive microenvironment and may be involved in primary resistance to anti-PD-1/anti-PD-L1, as it has been reported in lung cancer. The aim of this review is to discuss interactions of LKB1 with the tumor microenvironment and the potential applications of this knowledge in predicting response to treatment in lung cancer.
10.3390/ijms20081874
Impact of intracellular innate immune receptors on immunometabolism.
Cellular & molecular immunology
Immunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.
10.1038/s41423-021-00780-y
LKB1 and cancer: The dual role of metabolic regulation.
Li Ting-Ting,Zhu Hai-Bin
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Liver kinase B1 (LKB1) is an essential serine/threonine kinase frequently associated with Peutz-Jeghers syndrome (PJS). In this review, we provide an overview of the role of LKB1 in conferring protection to cancer cells against metabolic stress and promoting cancer cell survival and invasion. This carcinogenic effect contradicts the previous conclusion that LKB1 is a tumor suppressor gene. Here we try to explain the contradictory effect of LKB1 on cancer from a metabolic perspective. Upon deletion of LKB1, cancer cells experience increased energy as well as oxidative stress, thereby causing genomic instability. Meanwhile, mutated LKB1 cooperates with other metabolic regulatory genes to promote metabolic reprogramming that subsequently facilitates adaptation to strong metabolic stress, resulting in development of a more aggressive malignant phenotype. We aim to specifically discuss the contradictory role of LKB1 in cancer by reviewing the mechanism of LKB1 with an emphasis on metabolic stress and metabolic reprogramming.
10.1016/j.biopha.2020.110872
Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
Nature reviews. Cancer
The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy.
10.1038/s41568-019-0179-8
KRAS G12C-mutant driven non-small cell lung cancer (NSCLC).
Critical reviews in oncology/hematology
KRAS G12C mutations in non-small cell lung cancer (NSCLC) partially respond to KRAS G12C covalent inhibitors. However, early adaptive resistance occurs due to rewiring of signaling pathways, activating receptor tyrosine kinases, primarily EGFR, but also MET and ligands. Evidence indicates that treatment with KRAS G12C inhibitors (sotorasib) triggers the MRAS:SHOC2:PP1C trimeric complex. Activation of MRAS occurs from alterations in the Scribble and Hippo-dependent pathways, leading to YAP activation. Other mechanisms that involve STAT3 signaling are intertwined with the activation of MRAS. The high-resolution MRAS:SHOC2:PP1C crystallization structure allows in silico analysis for drug development. Activation of MRAS:SHOC2:PP1C is primarily Scribble-driven and downregulated by HUWE1. The reactivation of the MRAS complex is carried out by valosin containing protein (VCP). Exploring these pathways as therapeutic targets and their impact on different chemotherapeutic agents (carboplatin, paclitaxel) is crucial. Comutations in STK11/LKB1 often co-occur with KRAS G12C, jeopardizing the effect of immune checkpoint (anti-PD1/PDL1) inhibitors.
10.1016/j.critrevonc.2023.104228
LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective.
Ciccarese Francesco,Zulato Elisabetta,Indraccolo Stefano
Oxidative medicine and cellular longevity
Inactivating mutations of the tumor suppressor gene Liver Kinase B1 () are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.
10.1155/2019/8730816