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Molecular Cancer Research
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Cell Fate Decisions

β2-adrenoreceptor Signaling Increases Therapy Resistance in Prostate Cancer by Upregulating MCL1

Sazzad Hassan, Ashok Pullikuth, Kyle C. Nelson, Anabel Flores, Yelena Karpova, Daniele Baiz, Sinan Zhu, Guangchao Sui, Yue Huang, Young A. Choi, Ralph D'Agostino Jr, Ashok Hemal, Urs von Holzen, Waldemar Debinski and George Kulik
Sazzad Hassan
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
2Indiana University School of Medicine-South Bend, South Bend, Indiana.
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Ashok Pullikuth
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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  • ORCID record for Ashok Pullikuth
Kyle C. Nelson
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Anabel Flores
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Yelena Karpova
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Daniele Baiz
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Sinan Zhu
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Guangchao Sui
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Yue Huang
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Young A. Choi
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Ralph D'Agostino Jr
3Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Ashok Hemal
4Department of Urology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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Urs von Holzen
2Indiana University School of Medicine-South Bend, South Bend, Indiana.
5Goshen Center for Cancer Care, Goshen, Indiana.
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Waldemar Debinski
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
3Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, North Carolina.
6Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston-Salem, North Carolina.
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George Kulik
1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
3Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, North Carolina.
4Department of Urology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
7Department of Life Sciences, Alfaisal University, Riyadh, Kingdom of Saudi Arabia.
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  • For correspondence: gkulik@wakehealth.edu
DOI: 10.1158/1541-7786.MCR-19-1037 Published December 2020
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Abstract

There is accumulating evidence that continuous activation of the sympathetic nervous system due to psychosocial stress increases resistance to therapy and accelerates tumor growth via β2-adrenoreceptor signaling (ADRB2). However, the effector mechanisms appear to be specific to tumor type. Here we show that activation of ADRB2 by epinephrine, increased in response to immobilization stress, delays the loss of MCL1 apoptosis regulator (MCL1) protein expression induced by cytotoxic drugs in prostate cancer cells; and thus, increases resistance of prostate cancer xenografts to cytotoxic therapies. The effect of epinephrine on MCL1 protein depended on protein kinase A (PKA) activity, but was independent from androgen receptor expression. Furthermore, elevated blood epinephrine levels correlated positively with an increased MCL1 protein expression in human prostate biopsies. In summary, we demonstrate that stress triggers an androgen-independent antiapoptotic signaling via the ADRB2/PKA/MCL1 pathway in prostate cancer cells.

Implications: Presented results justify clinical studies of ADRB2 blockers as therapeutics and of MCL1 protein expression as potential biomarker predicting efficacy of apoptosis-targeting drugs in prostate cancer.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1839–48

  • Received October 20, 2019.
  • Revision received February 23, 2020.
  • Accepted September 10, 2020.
  • Published first September 14, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (12)
December 2020
Volume 18, Issue 12
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β2-adrenoreceptor Signaling Increases Therapy Resistance in Prostate Cancer by Upregulating MCL1
Sazzad Hassan, Ashok Pullikuth, Kyle C. Nelson, Anabel Flores, Yelena Karpova, Daniele Baiz, Sinan Zhu, Guangchao Sui, Yue Huang, Young A. Choi, Ralph D'Agostino Jr, Ashok Hemal, Urs von Holzen, Waldemar Debinski and George Kulik
Mol Cancer Res December 1 2020 (18) (12) 1839-1848; DOI: 10.1158/1541-7786.MCR-19-1037

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β2-adrenoreceptor Signaling Increases Therapy Resistance in Prostate Cancer by Upregulating MCL1
Sazzad Hassan, Ashok Pullikuth, Kyle C. Nelson, Anabel Flores, Yelena Karpova, Daniele Baiz, Sinan Zhu, Guangchao Sui, Yue Huang, Young A. Choi, Ralph D'Agostino Jr, Ashok Hemal, Urs von Holzen, Waldemar Debinski and George Kulik
Mol Cancer Res December 1 2020 (18) (12) 1839-1848; DOI: 10.1158/1541-7786.MCR-19-1037
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