TY - JOUR
T1 - ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts
AU - Washington, M. N.
AU - Suh, G.
AU - Orozco, A. F.
AU - Sutton, M. N.
AU - Yang, H.
AU - Wang, Y.
AU - Mao, W.
AU - Millward, S.
AU - Ornelas, A.
AU - Atkinson, N.
AU - Liao, W.
AU - Bast, R. C.
AU - Lu, Z.
N1 - Funding Information:
Acknowledgements. These studies were supported in part by a grant from the National Cancer Institute R01 CA135354, by the M.D. Anderson SPORE in Ovarian Cancer NCI P50 CA83639, the Shared Resources of the M.D. Anderson CCSG NCI P30 CA16672, the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers TL1TR000369 and UL1TR000371, the Ovarian Cancer Research Fund, the National Foundation for Cancer Research, the American Legion Auxiliary, and philanthropic support from the Zarrow Foundation, Stuart and Gaye Lynn Zarrow and the Chia Family Foundation.
Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015/8/6
Y1 - 2015/8/6
N2 - Autophagy can sustain or kill tumor cells depending upon the context. The mechanism of autophagy-associated cell death has not been well elucidated and autophagy has enhanced or inhibited sensitivity of cancer cells to cytotoxic chemotherapy in different models. ARHI (DIRAS3), an imprinted tumor suppressor gene, is downregulated in 60% of ovarian cancers. In cell culture, re-expression of ARHI induces autophagy and ovarian cancer cell death within 72 h. In xenografts, re-expression of ARHI arrests cell growth and induces autophagy, but does not kill engrafted cancer cells. When ARHI levels are reduced after 6 weeks, dormancy is broken and xenografts grow promptly. In this study, ARHI-induced ovarian cancer cell death in culture has been found to depend upon autophagy and has been linked to G1 cell-cycle arrest, enhanced reactive oxygen species (ROS) activity, RIP1/RIP3 activation and necrosis. Re-expression of ARHI enhanced the cytotoxic effect of cisplatin in cell culture, increasing caspase-3 activation and PARP cleavage by inhibiting ERK and HER2 activity and downregulating XIAP and Bcl-2. In xenografts, treatment with cisplatin significantly slowed the outgrowth of dormant autophagic cells after reduction of ARHI, but the addition of chloroquine did not further inhibit xenograft outgrowth. Taken together, we have found that autophagy-associated cancer cell death and autophagy-enhanced sensitivity to cisplatin depend upon different mechanisms and that dormant, autophagic cancer cells are still vulnerable to cisplatin-based chemotherapy.
AB - Autophagy can sustain or kill tumor cells depending upon the context. The mechanism of autophagy-associated cell death has not been well elucidated and autophagy has enhanced or inhibited sensitivity of cancer cells to cytotoxic chemotherapy in different models. ARHI (DIRAS3), an imprinted tumor suppressor gene, is downregulated in 60% of ovarian cancers. In cell culture, re-expression of ARHI induces autophagy and ovarian cancer cell death within 72 h. In xenografts, re-expression of ARHI arrests cell growth and induces autophagy, but does not kill engrafted cancer cells. When ARHI levels are reduced after 6 weeks, dormancy is broken and xenografts grow promptly. In this study, ARHI-induced ovarian cancer cell death in culture has been found to depend upon autophagy and has been linked to G1 cell-cycle arrest, enhanced reactive oxygen species (ROS) activity, RIP1/RIP3 activation and necrosis. Re-expression of ARHI enhanced the cytotoxic effect of cisplatin in cell culture, increasing caspase-3 activation and PARP cleavage by inhibiting ERK and HER2 activity and downregulating XIAP and Bcl-2. In xenografts, treatment with cisplatin significantly slowed the outgrowth of dormant autophagic cells after reduction of ARHI, but the addition of chloroquine did not further inhibit xenograft outgrowth. Taken together, we have found that autophagy-associated cancer cell death and autophagy-enhanced sensitivity to cisplatin depend upon different mechanisms and that dormant, autophagic cancer cells are still vulnerable to cisplatin-based chemotherapy.
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U2 - 10.1038/cddis.2015.208
DO - 10.1038/cddis.2015.208
M3 - Article
C2 - 26247722
AN - SCOPUS:84938893568
SN - 2041-4889
VL - 6
JO - Cell Death and Disease
JF - Cell Death and Disease
M1 - e1836
ER -