Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress.
Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC), but lesions larger than 2-3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS) are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC). Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dependent-protein kinase B (AKT) survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2)-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1)-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primary human HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3) and prognosis (AKT1). Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin.
Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Scott M
SM
Thompson
Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Matthew R
MR
Callstrom
Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Danielle E
DE
Jondal
Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Kim A
KA
Butters
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Bruce E
BE
Knudsen
Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Jill L
JL
Anderson
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Karen R
KR
Lien
Genomics Research Center, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Shari L
SL
Sutor
Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Ju-Seog
JS
Lee
Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
Snorri S
SS
Thorgeirsson
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Joseph P
JP
Grande
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
Lewis R
LR
Roberts
Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
David A
DA
Woodrum
D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D053148:Caspase 3; D053179:Caspase 7; D048049:Extracellular Signal-Regulated MAP Kinases; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases