Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress

• Published in: PloS one Vol. 11; no. 9; p. e0162634
• Main Authors: Thompson, Scott M, Callstrom, Matthew R, Jondal, Danielle E, Butters, Kim A, Knudsen, Bruce E, Anderson, Jill L, Lien, Karen R, Sutor, Shari L, Lee, Ju-Seog, Thorgeirsson, Snorri S, Grande, Joseph P, Roberts, Lewis R, Woodrum, David A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09-09-2016; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Ablation; Ablation (Surgery); AKT protein; AKT1 protein; Animals; Apoptosis; Biology and Life Sciences; Blotting, Western; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase 7 - genetics; Caspase 7 - metabolism; Cell cycle; Cell Line, Tumor; Cell Proliferation - genetics; Cell Proliferation - physiology; Cell survival; Cell Survival - genetics; Cell Survival - physiology; Consent; Drug dosages; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gangrene; Gene expression; Genomics; Heat; Heat stress; Heat tolerance; Hep G2 Cells; Hepatocellular carcinoma; Hepatocytes - metabolism; Hot Temperature; Humans; Inhibition; Isoforms; Kinases; Laboratories; Lesions; Liver cancer; Male; Mechanistic Target of Rapamycin Complex 2; Medical research; Medicine; Medicine and Health Sciences; Molecular modelling; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Oncogene Protein v-akt - genetics; Oncogene Protein v-akt - metabolism; Pathology; Patients; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Physical Sciences; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Rats; Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Stem cells; Studies; Survival; Thermal resistance; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0162634

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.