Low-dose arsenic-mediated metabolic shift is associated with activation of Polo-like kinase 1 (Plk1).
Arsenic is a well-established human carcinogen associated with cancers of the skin, liver, lung, kidney, and bladder. Although numerous carcinogenic pathways have been proposed, the molecular mechanisms underlying arsenic-associated cancer etiology are still elusive. The cellular responses to arsenic exposure are dose dependent. It was recently shown that low-dose arsenic leads to a metabolic shift from mitochondrial respiration to aerobic glycolysis via inactivation of tumor suppressor p53 and activation of NF-κB. However, how inactivation of p53, activation of NF-κB, and metabolic change are coordinated in response to low-dose arsenic exposure is still not completely understood. Polo-like kinase 1 (Plk1) is a well- documented regulator in many cell cycle-related events. Herein, we showed that low-dose arsenic leads to elevation of Plk1 in an NF-κB-dependent manner and that elevation of Plk1 contributes to the metabolic change from oxidative phosphorylation to glycolysis via activation of the PI3K/AKT/mTOR pathway. Furthermore, we showed that inhibition/depletion of Plk1 reverses low-dose arsenic-associated phenotypes, including enhanced cell proliferation, activation of the PI3K/AKT/mTOR pathway, and increased glycolysis. Finally, inhibition of the PI3K/AKT/mTOR pathway also antagonizes the enhanced glycolytic influx due to low-dose arsenic exposure. Our studies support the notion that Plk1 likely plays a critical role in cellular responses to low-dose arsenic.
a Department of Biochemistry ; Purdue University ; West Lafayette , IN USA.
Zhiguo
Z
Li
a Department of Biochemistry ; Purdue University ; West Lafayette , IN USA.|b School of Public Health; Xinjiang Medical University ; Urumqi, Xinjiang , China.
Ying
Y
Lu
c Department of Dermatology ; University of Wisconsin ; Madison , WI USA.
Nihal
N
Ahmad
d Department of Obstetrics and Gynecology ; J.W. Goethe University ; Frankfurt , Germany.
Klaus
K
Strebhardt
a Department of Biochemistry ; Purdue University ; West Lafayette , IN USA.|e Center for Cancer Research; Purdue University ; West Lafayette , IN USA.
Xiaoqi
X
Liu
D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D001151:Arsenic; D018797:Cell Cycle Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1
NF-κB; PI3K/AKT/mTOR pathway; Plk1; low-dose arsenic; metabolic shift