Single-dose neoadjuvant akt pathway inhibitor reduces growth of hepatocellular carcinoma after laser thermal ablation in small-animal model

Danielle E. Jondal, Scott M. Thompson, Kim A. Butters, Bruce E. Knudsen, Jill L. Anderson, Lewis Rowland Roberts, Matthew R Callstrom, David A Woodrum

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Abstract

Background: Local recurrence following thermal ablation of hepatocellular carcinoma (HCC) larger than 2-3 cm remains a challenging clinical problem. Prior studies suggest that phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)-dependent protein kinase B (AKT) signaling mediates HCC cell survival caused by moderate heat stress in vitro, but these findings need in vivo validation. Purpose: To test the hypothesis that neoadjuvant inhibition of PI3K/mTOR/AKT signaling reduces HCC tumor growth in vivo after laser ablation and to evaluate the effects of moderate heat stress on molecular signaling and cellular function in HCC cells in vitro. Materials and Methods: HCC tumor-bearing mice were randomized to neoadjuvant PI3K/mTOR inhibitor (BEZ235) or control groups followed by an intentional partial laser ablation or sham ablation; there were at least nine mice per group. Postablation tumor growth was monitored up to 7 days. Tumor volumes were compared for drug or ablation groups by using two-way analysis of variance. N1S1 HCC cells pretreated with BEZ235 or control and subjected to moderate heat stress (45°C for 10 minutes) or control (37°C for 10 minutes) were analyzed by using mass spectrometry. Protein interaction networks were derived from protein expression analysis software, and cellular function activation state (Z-score) and fold-change in AKT phosphorylation were calculated. Results: There was a 37%-75% reduction in HCC tumor volume by day 7 after ablation in the BEZ235 plus ablation group (713 mm3 ± 417) compared with vehicle plus sham (1559 mm3 ± 552), vehicle plus ablation (1041 mm3 ± 591), and BEZ235 plus sham (1108 mm3 ± 523) groups (P , .001, P = .04, and P = .005, respectively). PI3K/mTOR inhibition prevented moderate heat stress-induced AKT signaling (Z-score, 20.2; P , .001) and isoform-specific AKT phosphorylation compared with the vehicle plus heat stress group. PI3K/mTOR inhibition prevented moderate heat stress-induced global effects on HCC molecular signaling and cellular function, including decreased cell survival, growth, and proliferation (Z-score, 20.3 to 23.2; P , .001) and increased apoptosis and cell death (Z-score, 0.4-1.1; P , .001). Conclusion: Moderate heat stress induces PI3K/mTOR/AKT-dependent global effects on hepatocellular carcinoma (HCC) cell survival, function, and death. Neoadjuvant PI3K/mTOR/AKT inhibition reduces postablation HCC tumor growth.

Original languageEnglish (US)
Pages (from-to)752-759
Number of pages8
JournalRadiology
Volume292
Issue number3
DOIs
StatePublished - Jan 1 2019

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Growth Inhibitors
Laser Therapy
Hepatocellular Carcinoma
1-Phosphatidylinositol 4-Kinase
Animal Models
Hot Temperature
Sirolimus
Cell Survival
Growth
Tumor Burden
Neoplasms
Cell Death
TOR Serine-Threonine Kinases
Phosphorylation
Protein Interaction Maps
Proto-Oncogene Proteins c-akt
Mass Spectrometry
Analysis of Variance
Protein Isoforms
Software

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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Single-dose neoadjuvant akt pathway inhibitor reduces growth of hepatocellular carcinoma after laser thermal ablation in small-animal model. / Jondal, Danielle E.; Thompson, Scott M.; Butters, Kim A.; Knudsen, Bruce E.; Anderson, Jill L.; Roberts, Lewis Rowland; Callstrom, Matthew R; Woodrum, David A.

In: Radiology, Vol. 292, No. 3, 01.01.2019, p. 752-759.

Research output: Contribution to journalArticle

Jondal, Danielle E. ; Thompson, Scott M. ; Butters, Kim A. ; Knudsen, Bruce E. ; Anderson, Jill L. ; Roberts, Lewis Rowland ; Callstrom, Matthew R ; Woodrum, David A. / Single-dose neoadjuvant akt pathway inhibitor reduces growth of hepatocellular carcinoma after laser thermal ablation in small-animal model. In: Radiology. 2019 ; Vol. 292, No. 3. pp. 752-759.
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title = "Single-dose neoadjuvant akt pathway inhibitor reduces growth of hepatocellular carcinoma after laser thermal ablation in small-animal model",
abstract = "Background: Local recurrence following thermal ablation of hepatocellular carcinoma (HCC) larger than 2-3 cm remains a challenging clinical problem. Prior studies suggest that phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)-dependent protein kinase B (AKT) signaling mediates HCC cell survival caused by moderate heat stress in vitro, but these findings need in vivo validation. Purpose: To test the hypothesis that neoadjuvant inhibition of PI3K/mTOR/AKT signaling reduces HCC tumor growth in vivo after laser ablation and to evaluate the effects of moderate heat stress on molecular signaling and cellular function in HCC cells in vitro. Materials and Methods: HCC tumor-bearing mice were randomized to neoadjuvant PI3K/mTOR inhibitor (BEZ235) or control groups followed by an intentional partial laser ablation or sham ablation; there were at least nine mice per group. Postablation tumor growth was monitored up to 7 days. Tumor volumes were compared for drug or ablation groups by using two-way analysis of variance. N1S1 HCC cells pretreated with BEZ235 or control and subjected to moderate heat stress (45°C for 10 minutes) or control (37°C for 10 minutes) were analyzed by using mass spectrometry. Protein interaction networks were derived from protein expression analysis software, and cellular function activation state (Z-score) and fold-change in AKT phosphorylation were calculated. Results: There was a 37{\%}-75{\%} reduction in HCC tumor volume by day 7 after ablation in the BEZ235 plus ablation group (713 mm3 ± 417) compared with vehicle plus sham (1559 mm3 ± 552), vehicle plus ablation (1041 mm3 ± 591), and BEZ235 plus sham (1108 mm3 ± 523) groups (P , .001, P = .04, and P = .005, respectively). PI3K/mTOR inhibition prevented moderate heat stress-induced AKT signaling (Z-score, 20.2; P , .001) and isoform-specific AKT phosphorylation compared with the vehicle plus heat stress group. PI3K/mTOR inhibition prevented moderate heat stress-induced global effects on HCC molecular signaling and cellular function, including decreased cell survival, growth, and proliferation (Z-score, 20.3 to 23.2; P , .001) and increased apoptosis and cell death (Z-score, 0.4-1.1; P , .001). Conclusion: Moderate heat stress induces PI3K/mTOR/AKT-dependent global effects on hepatocellular carcinoma (HCC) cell survival, function, and death. Neoadjuvant PI3K/mTOR/AKT inhibition reduces postablation HCC tumor growth.",
author = "Jondal, {Danielle E.} and Thompson, {Scott M.} and Butters, {Kim A.} and Knudsen, {Bruce E.} and Anderson, {Jill L.} and Roberts, {Lewis Rowland} and Callstrom, {Matthew R} and Woodrum, {David A}",
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T1 - Single-dose neoadjuvant akt pathway inhibitor reduces growth of hepatocellular carcinoma after laser thermal ablation in small-animal model

AU - Jondal, Danielle E.

AU - Thompson, Scott M.

AU - Butters, Kim A.

AU - Knudsen, Bruce E.

AU - Anderson, Jill L.

AU - Roberts, Lewis Rowland

AU - Callstrom, Matthew R

AU - Woodrum, David A

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Local recurrence following thermal ablation of hepatocellular carcinoma (HCC) larger than 2-3 cm remains a challenging clinical problem. Prior studies suggest that phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)-dependent protein kinase B (AKT) signaling mediates HCC cell survival caused by moderate heat stress in vitro, but these findings need in vivo validation. Purpose: To test the hypothesis that neoadjuvant inhibition of PI3K/mTOR/AKT signaling reduces HCC tumor growth in vivo after laser ablation and to evaluate the effects of moderate heat stress on molecular signaling and cellular function in HCC cells in vitro. Materials and Methods: HCC tumor-bearing mice were randomized to neoadjuvant PI3K/mTOR inhibitor (BEZ235) or control groups followed by an intentional partial laser ablation or sham ablation; there were at least nine mice per group. Postablation tumor growth was monitored up to 7 days. Tumor volumes were compared for drug or ablation groups by using two-way analysis of variance. N1S1 HCC cells pretreated with BEZ235 or control and subjected to moderate heat stress (45°C for 10 minutes) or control (37°C for 10 minutes) were analyzed by using mass spectrometry. Protein interaction networks were derived from protein expression analysis software, and cellular function activation state (Z-score) and fold-change in AKT phosphorylation were calculated. Results: There was a 37%-75% reduction in HCC tumor volume by day 7 after ablation in the BEZ235 plus ablation group (713 mm3 ± 417) compared with vehicle plus sham (1559 mm3 ± 552), vehicle plus ablation (1041 mm3 ± 591), and BEZ235 plus sham (1108 mm3 ± 523) groups (P , .001, P = .04, and P = .005, respectively). PI3K/mTOR inhibition prevented moderate heat stress-induced AKT signaling (Z-score, 20.2; P , .001) and isoform-specific AKT phosphorylation compared with the vehicle plus heat stress group. PI3K/mTOR inhibition prevented moderate heat stress-induced global effects on HCC molecular signaling and cellular function, including decreased cell survival, growth, and proliferation (Z-score, 20.3 to 23.2; P , .001) and increased apoptosis and cell death (Z-score, 0.4-1.1; P , .001). Conclusion: Moderate heat stress induces PI3K/mTOR/AKT-dependent global effects on hepatocellular carcinoma (HCC) cell survival, function, and death. Neoadjuvant PI3K/mTOR/AKT inhibition reduces postablation HCC tumor growth.

AB - Background: Local recurrence following thermal ablation of hepatocellular carcinoma (HCC) larger than 2-3 cm remains a challenging clinical problem. Prior studies suggest that phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)-dependent protein kinase B (AKT) signaling mediates HCC cell survival caused by moderate heat stress in vitro, but these findings need in vivo validation. Purpose: To test the hypothesis that neoadjuvant inhibition of PI3K/mTOR/AKT signaling reduces HCC tumor growth in vivo after laser ablation and to evaluate the effects of moderate heat stress on molecular signaling and cellular function in HCC cells in vitro. Materials and Methods: HCC tumor-bearing mice were randomized to neoadjuvant PI3K/mTOR inhibitor (BEZ235) or control groups followed by an intentional partial laser ablation or sham ablation; there were at least nine mice per group. Postablation tumor growth was monitored up to 7 days. Tumor volumes were compared for drug or ablation groups by using two-way analysis of variance. N1S1 HCC cells pretreated with BEZ235 or control and subjected to moderate heat stress (45°C for 10 minutes) or control (37°C for 10 minutes) were analyzed by using mass spectrometry. Protein interaction networks were derived from protein expression analysis software, and cellular function activation state (Z-score) and fold-change in AKT phosphorylation were calculated. Results: There was a 37%-75% reduction in HCC tumor volume by day 7 after ablation in the BEZ235 plus ablation group (713 mm3 ± 417) compared with vehicle plus sham (1559 mm3 ± 552), vehicle plus ablation (1041 mm3 ± 591), and BEZ235 plus sham (1108 mm3 ± 523) groups (P , .001, P = .04, and P = .005, respectively). PI3K/mTOR inhibition prevented moderate heat stress-induced AKT signaling (Z-score, 20.2; P , .001) and isoform-specific AKT phosphorylation compared with the vehicle plus heat stress group. PI3K/mTOR inhibition prevented moderate heat stress-induced global effects on HCC molecular signaling and cellular function, including decreased cell survival, growth, and proliferation (Z-score, 20.3 to 23.2; P , .001) and increased apoptosis and cell death (Z-score, 0.4-1.1; P , .001). Conclusion: Moderate heat stress induces PI3K/mTOR/AKT-dependent global effects on hepatocellular carcinoma (HCC) cell survival, function, and death. Neoadjuvant PI3K/mTOR/AKT inhibition reduces postablation HCC tumor growth.

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