Heat Stress-InducedPI3K/mTORC2-Dependent AKT signaling is a central mediator of hepatocellular carcinoma survival to thermal ablation induced heat stress

Scott M. Thompson, Matthew R Callstrom, Danielle E. Jondal, Kim A. Butters, Bruce E. Knudsen, Jill L. Anderson, Karen R. Lien, Shari L. Sutor, Ju Seog Lee, Snorri S. Thorgeirsson, Joseph Peter Grande, Lewis Rowland Roberts, David A Woodrum

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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 primaryhuman 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.

Original languageEnglish (US)
Article numbere0162634
JournalPLoS One
Volume11
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

hepatoma
Ablation
heat stress
Hepatocellular Carcinoma
Hot Temperature
heat
Survival
Phosphatidylinositols
1-Phosphatidylinositol 4-Kinase
phosphatidylinositol 3-kinase
Phosphotransferases
Cells
Recurrence
cells
Tumors
hepatocytes
adjuvants
Hepatocytes
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Heat Stress-InducedPI3K/mTORC2-Dependent AKT signaling is a central mediator of hepatocellular carcinoma survival to thermal ablation induced heat stress. / 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 Peter; Roberts, Lewis Rowland; Woodrum, David A.

In: PLoS One, Vol. 11, No. 9, e0162634, 01.09.2016.

Research output: Contribution to journalArticle

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 Peter ; Roberts, Lewis Rowland ; Woodrum, David A. / Heat Stress-InducedPI3K/mTORC2-Dependent AKT signaling is a central mediator of hepatocellular carcinoma survival to thermal ablation induced heat stress. In: PLoS One. 2016 ; Vol. 11, No. 9.
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abstract = "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 primaryhuman 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.",
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AU - Anderson, Jill L.

AU - Lien, Karen R.

AU - Sutor, Shari L.

AU - Lee, Ju Seog

AU - Thorgeirsson, Snorri S.

AU - Grande, Joseph Peter

AU - Roberts, Lewis Rowland

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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 primaryhuman 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.

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