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Insulin‐like growth factor (IGF)‐I rescues breast cancer cells from chemotherapy‐induced cell death – proliferative and anti‐apoptotic effects

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Abstract

Insulin‐like growth factor (IGF)‐I protects many cell types from apoptosis. As a result, it is possible that IGF‐I‐responsive cancer cells may be resistant to apoptosis‐inducing chemotherapies. Therefore, we examined the effects of IGF‐I on paclitaxel and doxorubicin‐induced apoptosis in the IGF‐I‐responsive breast cancer cell line MCF‐7. Both drugs caused DNA laddering in a dose‐dependent fashion, and IGF‐I reduced the formation of ladders. We next examined the effects of IGF‐I and estradiol on cell survival following drug treatment in monolayer culture. IGF‐I, but not estradiol, increased survival of MCF‐7 cells in the presence of either drug. Cell cycle progression and counting of trypan‐blue stained cells showed that IGF‐I was inducing proliferation in paclitaxel‐treated but not doxorubicin‐treated cells. However, IGF‐I decreased the fraction of apoptotic cells in doxorubicin‐ but not paclitaxel‐treated cells. Recent work has shown that mitogen‐activated protein kinase (MAPK) and phosphotidylinositol‐3 (PI‐3) kinase are activated by IGF‐I in these cells. PI‐3 kinase activation has been linked to anti‐apoptotic functions while MAPK activation is associated with proliferation. We found that IGF‐I rescue of doxorubicin‐induced apoptosis required PI‐3 kinase but not MAPK function, suggesting that IGF‐I inhibited apoptosis. In contrast, IGF‐I rescue of paclitaxel‐induced apoptosis required both PI‐3 kinase and MAPK, suggesting that IGF‐I‐mediated protection was due to enhancement of proliferation. Therefore, IGF‐I attenuated the response of breast cancer cells to doxorubicin and paclitaxel by at least two mechanisms: induction of proliferation and inhibition of apoptosis. Thus, inhibition of IGF‐I action could be a useful adjuvant to cytotoxic chemotherapy in breast cancer.

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Authors and Affiliations

  1. Department of Medicine/Division of Medical Oncology, University of Texas Health Science Center, San Antonio, TX, USA

    Jennifer L. Gooch & Douglas Yee

  2. School of Pharmacy, University of Colorado Health Science Center, Denver, CO, USA

    Carla L. Van Den Berg

Authors
  1. Jennifer L. Gooch
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  2. Carla L. Van Den Berg
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  3. Douglas Yee
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Gooch, J.L., Van Den Berg, C.L. & Yee, D. Insulin‐like growth factor (IGF)‐I rescues breast cancer cells from chemotherapy‐induced cell death – proliferative and anti‐apoptotic effects. Breast Cancer Res Treat 56, 1–10 (1999). https://doi.org/10.1023/A:1006208721167

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  • DOI: https://doi.org/10.1023/A:1006208721167

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