The role of LKB1 in the maintenance of genomic stability.

Summary

Principal Investigator: Zhi Xiang Xu
Affiliation: University of Alabama at Birmingham
Country: USA
Abstract: DESCRIPTION (provided by applicant): (Also known as serine/threonine kinase 11, STK11) tumor suppressor is mutationally inactivated in Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by gastrointestinal polyps, mucocutaneous pigmentation, and a markedly increased risk for malignant tumors. Inactivating mutations in LKB1 are also found in cancer patients without PJS, including sporadic lung adenocarcinoma (common), ovarian cancer, breast cancer, pancreatic cancer, and biliary adenocarcinoma (rare). Although LKB1 encodes a protein kinase to which a variety of functions have been ascribed, as yet no unifying hypothesis has convincingly explained how loss of LKB1 function contributes to carcinogenesis. Therefore, the long-term goal of this project is to identify the molecular mechanism underlying the tumor suppressor function of LKB1, a prerequisite for targeting LKB1 function in cancer treatment. In the last decade, considerable evidence has accumulated suggesting that genomic instability plays an important role in tumorigenesis. Supporting a role in tumor suppression, our preliminary findings suggest that LKB1 plays a critical role in maintaining genomic stability. We found that LKB1 interacts with ATM, BRCA1, and other DNA damage response (DDR) proteins in vivo. LKB1-deficient cells exhibit a delayed DDR and reduced DNA repair after exposure to ionizing radiation (IR). LKB1 deficiency enhances intracellular reactive oxygen species (ROS) accumulation, which is a major cause of DNA damage and genetic instability. Ectopic expression of LKB1 reduces intracellular ROS levels. Based on these observations, we hypothesize that LKB1 suppresses tumorigenesis by safeguarding genomic stability through regulating DNA damage/repair response and inhibiting intracellular ROS production. We have designed the following specific aims to test our hypothesis. (1) Determine the role of LKB1 in IR- induced DNA damage/repair response. Hypothesis to be tested: LKB1 is a DDR protein that regulates the enzymes involved in DNA-damage repair and DNA replication. As a corollary, loss of LKB1 may lead to an accumulation of DNA damage, an increase in genomic instability, and augmented tumorigenesis. (2) Determine the role of ROS in the function of LKB1. Hypothesis to be tested: LKB1 protects the genome from ROS-induced oxidative stress by regulating antioxidant gene production. (3) Determine the protein signatures and signaling networks in IR- and H2O2- treated cells in the presence or absence of LKB1 and identify novel LKB1-interacting proteins under stressed conditions. Hypothesis to be tested: LKB1 interacts with specific proteins to mediate its role in the maintenance of genomic stability. Significance. Accomplishment of these objectives would suggest that LKB1 integrates different signals (DNA damage response, DNA repair, and antioxidant) and interacts with specific proteins in the maintenance of genomic stability. The findings should lead to a better understanding of the role that LKB1 mutation may play in the pathogenesis of PJS and tumorigenesis. These studies will also provide rationale for pharmacologic replacement or mimicry of LKB1 function in cancer prevention and treatment. PUBLIC HEALTH RELEVANCE: LKB1 is a serine/threonine kinase that is mutationally inactivated in Peutz-Jeghers syndrome and many cancers. It is estimated that 93% of PJS patients will develop a malignant tumor at an average age of 43 years 3. Also, more than a third of sporadic lung adenocarcinomas have been reported to have LKB1 mutations 5, 6. Although a variety of functions have been ascribed to LKB1, as yet no individual hypothesis has convincingly explained how loss of LKB1 function contributes to carcinogenesis. Thus, the long-term objective of this project is to identify the molecular mechanism underlying LKB1's tumor suppressor function, a prerequisite for the development of pharmacological agents that can modulate or mimic LKB1 function for cancer prevention and treatment. Based on our preliminary studies, we hypothesize that LKB1 suppresses tumorigenesis by safeguarding genomic stability through its regulation of the DNA damage/repair response and inhibition of intracellular ROS generation. In light of the high incidence of LKB1 mutations in primary human tumors of diverse origin, understanding the functional roles of LKB1 in genome stability will provide valuable new information to further our current knowledge of carcinogenesis and cancer therapy. Thus, the findings from these studies will be widely applicable.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Metformin impairs the growth of liver kinase B1-intact cervical cancer cells
    XuXian Xiao
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Gynecol Oncol 127:249-55. 2012
  2. pmc MIR106B and MIR93 prevent removal of bacteria from epithelial cells by disrupting ATG16L1-mediated autophagy
    Changming Lu
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama
    Gastroenterology 146:188-99. 2014
  3. pmc Piperlongumine induces autophagy by targeting p38 signaling
    Y Wang
    Division of Hematology and Oncology, Comprehensive Cancer Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
    Cell Death Dis 4:e824. 2013
  4. pmc Targeting the LKB1 tumor suppressor
    Rui Xun Zhao
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Wallace Tumor Institute Building, Room 520D, Birmingham, AL 35294, USA
    Curr Drug Targets 15:32-52. 2014
  5. ncbi Liver kinase B1 regulates the centrosome via PLK1
    K Werle
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Cell Death Dis 5:e1157. 2014
  6. pmc Avicin D, a plant triterpenoid, induces cell apoptosis by recruitment of Fas and downstream signaling molecules into lipid rafts
    Zhi Xiang Xu
    Department of Systems Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas, USA
    PLoS ONE 4:e8532. 2009
  7. pmc PARP1 inhibitors attenuate AKT phosphorylation via the upregulation of PHLPP1
    Shuai Wang
    State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    Biochem Biophys Res Commun 412:379-84. 2011

Scientific Experts

  • Zhi Xiang Xu
  • Rui Xun Zhao
  • Changming Lu
  • Jiyong Liang
  • Rutao Cui
  • K Werle
  • H G Xu
  • Y L Li
  • J Chen
  • R Cui
  • Q He
  • R X Zhao
  • J Liang
  • JianFeng Chen
  • QiongQiong He
  • Kaitlin D Werle
  • Y Wang
  • XuXian Xiao
  • Ben C Davis
  • Shuai Wang
  • Boxin Xue
  • Yong Wang
  • C Lu
  • Yuxi Shan
  • Hua Guo Xu
  • Xianzheng Zhou
  • Guoqing Jiang
  • Yu Lin Li
  • X Xiao
  • G Jiang
  • K D Werle
  • J W Wang
  • B Xue
  • Y Shan
  • Sai Juan Chen
  • Huibo Wang

Detail Information

Publications8

  1. pmc Metformin impairs the growth of liver kinase B1-intact cervical cancer cells
    XuXian Xiao
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Gynecol Oncol 127:249-55. 2012
    ..Recent investigations demonstrated that application of metformin reduces cancer risk. The present study aimed to determine the role of liver kinase B1 (LKB1) in the response of cervical cancer cells to metformin...
  2. pmc MIR106B and MIR93 prevent removal of bacteria from epithelial cells by disrupting ATG16L1-mediated autophagy
    Changming Lu
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama
    Gastroenterology 146:188-99. 2014
    ....
  3. pmc Piperlongumine induces autophagy by targeting p38 signaling
    Y Wang
    Division of Hematology and Oncology, Comprehensive Cancer Center, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
    Cell Death Dis 4:e824. 2013
    ..Thus, we have characterized a new mechanism for PL-induced cell death through the ROS-p38 pathway. Our findings support the therapeutic potential of PL by triggering autophagic cell death. ..
  4. pmc Targeting the LKB1 tumor suppressor
    Rui Xun Zhao
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Wallace Tumor Institute Building, Room 520D, Birmingham, AL 35294, USA
    Curr Drug Targets 15:32-52. 2014
    ..Within this review, several agents with potential activity against aberrant LKB1 signaling have been discussed. Potential strategies and challenges in targeting LKB1 inactivation are also considered. ..
  5. ncbi Liver kinase B1 regulates the centrosome via PLK1
    K Werle
    Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Cell Death Dis 5:e1157. 2014
    ..Expression of LKB1 is reversely correlated with the levels of PLK1 in human cancer tissues. Thus, we have uncovered a novel function of LKB1 in the maintenance of genomic stability through the regulation of centrosome mediated by PLK1. ..
  6. pmc Avicin D, a plant triterpenoid, induces cell apoptosis by recruitment of Fas and downstream signaling molecules into lipid rafts
    Zhi Xiang Xu
    Department of Systems Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas, USA
    PLoS ONE 4:e8532. 2009
    ..Taken together, our results demonstrate that avicin D triggers the redistribution of Fas in the membrane lipid rafts, where Fas activates receptor-mediated cell death...
  7. pmc PARP1 inhibitors attenuate AKT phosphorylation via the upregulation of PHLPP1
    Shuai Wang
    State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    Biochem Biophys Res Commun 412:379-84. 2011
    ..Therefore, our findings not only show the robust role of PARP1 inhibitors in AKT inhibition but also develop a novel strategy to increase the effectiveness of cancer treatment via PARP1 inhibitor-induced PHLPP1 upregulation...