Insulin receptor substrate 1 expression enhances the sensitivity of 32D cells to chemotherapy-induced cell death

Journal Article · Wed Aug 15 00:00:00 EDT 2012 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2012.04.020· OSTI ID:22212284

Porter, Holly A., E-mail: [e-mail] ^[1]; Molecular Medicine Program, University of Maryland School of Medicine, Baltimore, MD 21201 ^[2]; Carey, Gregory B., E-mail: [e-mail] ^[1]; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201 ^[2]; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201 ^[2]; Keegan, Achsah D., E-mail: [e-mail] ^[1]; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201 ^[2]; Molecular Medicine Program, University of Maryland School of Medicine, Baltimore, MD 21201 ^[2]; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201 ^[2]

---

1. Center for Vascular and Inflammatory Diseases, 800 West Baltimore Street, Room 318, Baltimore, MD 21201 (United States)
2. (United States)

The adapters IRS1 and IRS2 link growth factor receptors to downstream signaling pathways that regulate proliferation and survival. Both suppress factor-withdrawal-induced apoptosis and have been implicated in cancer progression. However, recent studies suggest IRS1 and IRS2 mediate differential functions in cancer pathogenesis. IRS1 promoted breast cancer proliferation, while IRS2 promoted metastasis. The role of IRS1 and IRS2 in controlling cell responses to chemotherapy is unknown. To determine the role of IRS1 and IRS2 in the sensitivity of cells to chemotherapy, we treated 32D cells lacking or expressing IRS proteins with various concentrations of chemotherapeutic agents. We found that expression of IRS1, in contrast to IRS2, enhanced the sensitivity of 32D cells to chemotherapy-induced apoptosis. When IRS2 was expressed with IRS1, the cells no longer showed enhanced sensitivity. Expression of IRS1 did not alter the expression of pro- and anti-apoptotic proteins; however, 32D-IRS1 cells expressed higher levels of Annexin A2. In 32D-IRS1 cells, IRS1 and Annexin A2 were both located in cytoplasmic and membrane fractions. We also found that IRS1 coprecipitated with Annexin A2, while IRS2 did not. Decreasing Annexin A2 levels reduced 32D-IRS1 cell sensitivity to chemotherapy. These results suggest IRS1 enhances sensitivity to chemotherapy in part through Annexin A2. -- Highlights: Black-Right-Pointing-Pointer IRS1 enhanced the sensitivity of 32D cells to chemotherapy-induced apoptosis. Black-Right-Pointing-Pointer This sensitivity is abrogated by the expression of IRS2. Black-Right-Pointing-Pointer Expressing IRS1 in 32D cells increased levels of Annexin A2. Black-Right-Pointing-Pointer Both IRS1 and Annexin A2 were located in cytoplasmic and membrane fractions. Black-Right-Pointing-Pointer Decreasing Annexin A2 in 32D-IRS1 cells abated their sensitivity to chemotherapy.

• OSTI ID: 22212284
• Journal Information: Experimental Cell Research, Vol. 318, Issue 14; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL PROLIFERATION
CHEMOTHERAPY
CONCENTRATION RATIO
GROWTH FACTORS
INSULIN
MAMMARY GLANDS
NEOPLASMS
RECEPTORS
SENSITIVITY
SUBSTRATES