Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics

Liwei Lang, Chloe Shay, Xiangdong Zhao, Yong Teng

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Although major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefore, the identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Activation of small GTPases such as Ras and Arf1 is a critical component of the signaling pathways for most of the receptors shown to be upregulated in advanced prostate cancer. Methods: The drug effects on cell proliferation were measured by CellTiter 96® AQueous One Solution Cell Proliferation Assay. The drug effects on cell migration and invasion were determined by Radius™ 24-well and Matrigel-coated Boyden chambers. The drug effects on apoptosis were assessed by FITC Annexin V Apoptosis Detection Kit with 7-AAD and Western blot with antibodies against cleaved PARP and Caspase 3. A NOD/SCID mouse model generated by subcutaneous injection was used to assess the in vivo drug efficacy in tumor growth. ERK activation and tumor cell proliferation in xenografts were examined by immunohistochemistry. Results: We show that Exo2, a small-molecule inhibitor that reduces Arf1 activation, effectively suppresses prostate cancer cell proliferation by blocking ERK1/2 activation. Exo2 also has other effects, inhibiting migration and invasion of PCA cells and inducing apoptosis. The Ras inhibitor salirasib augments Exo2-induced cytotoxicity in prostate cancer cells partially by enhancing the suppression of ERK1/2 phosphorylation. In a xenograft mouse model of prostate cancer, Exo2 reduces prostate tumor burden and inhibits ERK1/2 activation at a dose of 20 mg/kg. Synergistic treatment of salirasib and Exo2 exhibits a superior inhibitory effect on prostate tumor growth compared with either drug alone, which may be attributed to the more efficient inhibition of ERK1/2 phosphorylation. Conclusion: This study suggests that simultaneous blockade of Arf1 and Ras activation in prostate cancer cells is a potential targeted therapeutic strategy for preventing prostate cancer development.

Original languageEnglish (US)
Article number112
JournalJournal of Experimental and Clinical Cancer Research
Volume36
Issue number1
DOIs
StatePublished - Aug 23 2017

Fingerprint

Prostatic Neoplasms
Cell Proliferation
Therapeutics
Pharmaceutical Preparations
Apoptosis
Heterografts
Prostate
Neoplasms
Phosphorylation
Inbred NOD Mouse
Passive Cutaneous Anaphylaxis
SCID Mice
Monomeric GTP-Binding Proteins
Fluorescein-5-isothiocyanate
Annexin A5
Subcutaneous Injections
Growth
Tumor Burden
Caspase 3
Cell Movement

Keywords

  • Arf1
  • Combination treatment
  • Exo2
  • Prostate cancer
  • Ras
  • Salirasib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics. / Lang, Liwei; Shay, Chloe; Zhao, Xiangdong; Teng, Yong.

In: Journal of Experimental and Clinical Cancer Research, Vol. 36, No. 1, 112, 23.08.2017.

Research output: Contribution to journalArticle

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abstract = "Background: Although major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefore, the identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Activation of small GTPases such as Ras and Arf1 is a critical component of the signaling pathways for most of the receptors shown to be upregulated in advanced prostate cancer. Methods: The drug effects on cell proliferation were measured by CellTiter 96{\circledR} AQueous One Solution Cell Proliferation Assay. The drug effects on cell migration and invasion were determined by Radius™ 24-well and Matrigel-coated Boyden chambers. The drug effects on apoptosis were assessed by FITC Annexin V Apoptosis Detection Kit with 7-AAD and Western blot with antibodies against cleaved PARP and Caspase 3. A NOD/SCID mouse model generated by subcutaneous injection was used to assess the in vivo drug efficacy in tumor growth. ERK activation and tumor cell proliferation in xenografts were examined by immunohistochemistry. Results: We show that Exo2, a small-molecule inhibitor that reduces Arf1 activation, effectively suppresses prostate cancer cell proliferation by blocking ERK1/2 activation. Exo2 also has other effects, inhibiting migration and invasion of PCA cells and inducing apoptosis. The Ras inhibitor salirasib augments Exo2-induced cytotoxicity in prostate cancer cells partially by enhancing the suppression of ERK1/2 phosphorylation. In a xenograft mouse model of prostate cancer, Exo2 reduces prostate tumor burden and inhibits ERK1/2 activation at a dose of 20 mg/kg. Synergistic treatment of salirasib and Exo2 exhibits a superior inhibitory effect on prostate tumor growth compared with either drug alone, which may be attributed to the more efficient inhibition of ERK1/2 phosphorylation. Conclusion: This study suggests that simultaneous blockade of Arf1 and Ras activation in prostate cancer cells is a potential targeted therapeutic strategy for preventing prostate cancer development.",
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