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Perifosine inhibits S6K1–Gli1 signaling and enhances gemcitabine-induced anti-pancreatic cancer efficiency

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Abstract

Purpose

The pancreatic cancer has extremely low overall 5-year survival, and gemcitabine is the only approved single agent for pancreatic cancer treatment.

Methods

In the present study, we investigated the potential effect of perifosine, a novel Akt inhibitor on gemcitabine-induced anti-pancreatic cancer effect both in vivo and in vitro.

Results

We showed that sub-cytotoxic low concentration of perifosine dramatically enhanced gemcitabine-induced cytotoxicity in cultured pancreatic cancer cells. Perifosine inhibited Akt–mammalian target of rapamycin and Erk–mitogen-activated protein kinase activation in pancreatic cancer cells. Meanwhile, perifosine suppressed the hedgehog signaling, as it inhibited glioma-associated oncogenes (Gli) 1 activation and decreased its target protein patched 1 (PTCH1) expression. Our data demonstrated that perifosine blocked p70S6K1 (S6K1) activation, thus disrupting S6K1–Gli1 association and subsequent Gli1 activation. The reduction of S6K1 or Gli1 expression by target siRNAs inhibited PTCH1 expression and enhanced gemcitabine-induced cytotoxicity in pancreatic cancer cells. Significantly, perifosine dramatically enhanced gemcitabine-mediated antitumor effect in a PANC-1 xenograft severe combined immunodeficiency mice model.

Conclusions

In summary, we conclude that perifosine sensitizes gemcitabine-mediated anti-pancreatic cancer efficiency through regulating multiple signaling pathways.

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Abbreviations

Gli:

Glioma-associated oncogenes

mTOR:

Mammalian target of rapamycin

MAPK:

Mitogen-activated protein kinase

Hh:

Hedgehog

CCK-8:

Cell counting kit-8

SMO:

Smoothened

Sufu:

Suppressor of fused

PTCH1:

Patched 1

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Acknowledgments

This work was supported by the talent plan of Science and Technology Bureau of Zhejiang Province (2012R10043). The founders have no roles in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Conflict of interest

No conflict of interests are stated.

Author information

Authors and Affiliations

  1. Department of Thyroid and Breast Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, 310014, Zhejiang, China

    Ying Xin

  2. Office of Research, Zhejiang Medical College, Hangzhou, 310053, Zhejiang, China

    Xiang-di Shen

  3. Department of Interventional Radiology, The Second Affiliated Hospital of Soochow University, No. 1055 San Xiang Road, Suzhou, 215004, Jiangsu, China

    Long Cheng

  4. Department of Hepatobiliary Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, 310014, Zhejiang, China

    De-fei Hong

  5. Department of General Surgery, No.1 People’s Hospital of Hangzhou, No. 70 Kaiyuan Road, Xiaoshan District, Hangzhou, 310014, Zhejiang, China

    Bin Chen

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  1. Ying Xin
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  2. Xiang-di Shen
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  3. Long Cheng
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  4. De-fei Hong
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  5. Bin Chen
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Correspondence to Long Cheng or Bin Chen.

Additional information

Ying Xin, Xiang-di Shen and Long Cheng are Co-first authors.

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Xin, Y., Shen, Xd., Cheng, L. et al. Perifosine inhibits S6K1–Gli1 signaling and enhances gemcitabine-induced anti-pancreatic cancer efficiency. Cancer Chemother Pharmacol 73, 711–719 (2014). https://doi.org/10.1007/s00280-014-2397-9

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  • DOI: https://doi.org/10.1007/s00280-014-2397-9

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