PMID- 27611696 OWN - NLM STAT- MEDLINE DCOM- 20170828 LR - 20211204 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 9 DP - 2016 TI - Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress. PG - e0162634 LID - 10.1371/journal.pone.0162634 [doi] LID - e0162634 AB - 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. FAU - Thompson, Scott M AU - Thompson SM AD - Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Callstrom, Matthew R AU - Callstrom MR AD - Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Jondal, Danielle E AU - Jondal DE AD - Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Butters, Kim A AU - Butters KA AD - Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Knudsen, Bruce E AU - Knudsen BE AD - Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Anderson, Jill L AU - Anderson JL AD - Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Lien, Karen R AU - Lien KR AD - Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Sutor, Shari L AU - Sutor SL AD - Genomics Research Center, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Lee, Ju-Seog AU - Lee JS AD - Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. FAU - Thorgeirsson, Snorri S AU - Thorgeirsson SS AD - Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America. FAU - Grande, Joseph P AU - Grande JP AD - Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Roberts, Lewis R AU - Roberts LR AD - Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. FAU - Woodrum, David A AU - Woodrum DA AD - Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. LA - eng GR - C06 RR018898/RR/NCRR NIH HHS/United States GR - TL1 TR000137/TR/NCATS NIH HHS/United States GR - R01 CA177686/CA/NCI NIH HHS/United States GR - TL1 RR024152/RR/NCRR NIH HHS/United States GR - UL1 RR024150/RR/NCRR NIH HHS/United States PT - Journal Article DEP - 20160909 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Multiprotein Complexes) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.4.22.- (Caspase 3) RN - EC 3.4.22.- (Caspase 7) SB - IM MH - Animals MH - Blotting, Western MH - Carcinoma, Hepatocellular/genetics/*metabolism MH - Caspase 3/genetics/metabolism MH - Caspase 7/genetics/metabolism MH - Cell Line, Tumor MH - Cell Proliferation/genetics/physiology MH - Cell Survival/genetics/physiology MH - Extracellular Signal-Regulated MAP Kinases/genetics/metabolism MH - Hep G2 Cells MH - Hepatocytes/metabolism MH - *Hot Temperature MH - Humans MH - Male MH - Mechanistic Target of Rapamycin Complex 2 MH - Multiprotein Complexes/genetics/*metabolism MH - Oncogene Protein v-akt/genetics/*metabolism MH - Phosphatidylinositol 3-Kinases/genetics/*metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Rats MH - Signal Transduction/genetics/physiology MH - TOR Serine-Threonine Kinases/genetics/*metabolism PMC - PMC5017586 COIS- The authors have declared that no competing interests exist. EDAT- 2016/09/10 06:00 MHDA- 2017/08/29 06:00 PMCR- 2016/09/09 CRDT- 2016/09/10 06:00 PHST- 2016/06/24 00:00 [received] PHST- 2016/08/25 00:00 [accepted] PHST- 2016/09/10 06:00 [entrez] PHST- 2016/09/10 06:00 [pubmed] PHST- 2017/08/29 06:00 [medline] PHST- 2016/09/09 00:00 [pmc-release] AID - PONE-D-16-23062 [pii] AID - 10.1371/journal.pone.0162634 [doi] PST - epublish SO - PLoS One. 2016 Sep 9;11(9):e0162634. doi: 10.1371/journal.pone.0162634. eCollection 2016.