TY - JOUR
T1 - Inhibition of age-related therapy resistance in melanoma by rosiglitazone-mediated induction of klotho
AU - Behera, Reeti
AU - Kaur, Amanpreet
AU - Webster, Marie R.
AU - Kim, Suyeon
AU - Ndoye, Abibatou
AU - Kugel, Curtis H.
AU - Alicea, Gretchen M.
AU - Wang, Joshua
AU - Ghosh, Kanad
AU - Cheng, Phil
AU - Lisanti, Sofia
AU - Marchbank, Katie
AU - Dang, Vanessa
AU - Levesque, Mitchell
AU - Dummer, Reinhard
AU - Xu, Xiaowei
AU - Herlyn, Meenhard
AU - Aplin, Andrew E.
AU - Roesch, Alexander
AU - Caino, Cecilia
AU - Altieri, Dario C.
AU - Weeraratna, Ashani T.
N1 - Funding Information:
A.E. Aplin reports receiving commercial research grants from Pfizer Inc. A. Roesch reports receiving commercial research grants from Novartis. A.T. Weeraratna is a consultant/advisory board member for Phoremost Technologies. No potential conflicts of interest were disclosed by the other authors. We thank Dr. Gideon Bollag of Plexxikon for PLX4720. We thank Dmitry Gourevitch of the Wistar Histology Core and Fred Keeney of the Wistar Imaging facility. This work was supported in part by RO1 CA174746-01 (A.T. Weeraratna and R. Behera), P01 CA 114046-06 (A.T. Weeraratna and M. Herlyn), T32 CA 9171-36 (M.R. Webster and C.H. Kugel III), an MRF Established Investigator award (A.T. Weeraratna), an ACS-IRG award (A.T. Weeraratna), a Miriam and Sheldon Adelson Research Foundation Award (A.E. Aplin and M. Herlyn), P50 CA174523-01 (A.T. Weeraratna, X. Xu, and M. Herlyn), and R01-CA1826635 (A.E. Aplin). Core facilities at The Wistar Institute are supported by the CCSG grant P30 CA010815. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - Purpose: Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment could be an effective strategy for the treatment of melanoma. Experimental Design: PPARg increases klotho levels and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/Wnt5A cross-talk, in vitro and in vivo, and the implications of that for targeted therapy in young versus aged animals. Results: We show that rosiglitazone increases klotho and decreases Wnt5A in tumor cells, reducing the burden of both BRAF inhibitor-sensitive and BRAF inhibitor-resistant tumors in aged, but not young mice. However, when used in combination with PLX4720, tumor burden was reduced in both young and aged mice, even in resistant tumors. Conclusions: Using glitazones as adjuvant therapy for melanoma may provide a new treatment strategy for older melanoma patients who have developed resistance to vemurafenib. As klotho has been shown to play a role in other cancers too, our results may have wide relevance for multiple tumor types.
AB - Purpose: Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment could be an effective strategy for the treatment of melanoma. Experimental Design: PPARg increases klotho levels and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/Wnt5A cross-talk, in vitro and in vivo, and the implications of that for targeted therapy in young versus aged animals. Results: We show that rosiglitazone increases klotho and decreases Wnt5A in tumor cells, reducing the burden of both BRAF inhibitor-sensitive and BRAF inhibitor-resistant tumors in aged, but not young mice. However, when used in combination with PLX4720, tumor burden was reduced in both young and aged mice, even in resistant tumors. Conclusions: Using glitazones as adjuvant therapy for melanoma may provide a new treatment strategy for older melanoma patients who have developed resistance to vemurafenib. As klotho has been shown to play a role in other cancers too, our results may have wide relevance for multiple tumor types.
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U2 - 10.1158/1078-0432.CCR-17-0201
DO - 10.1158/1078-0432.CCR-17-0201
M3 - Article
C2 - 28232477
AN - SCOPUS:85020914898
VL - 23
SP - 3181
EP - 3190
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 12
ER -