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Inhibition of age-related therapy resistance in melanoma by rosiglitazone-mediated induction of Klotho


Abstract

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. 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: PPARγ increases klotho levels, and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/ Wnt5A crosstalk, in vitro and in vivo, and the implications of that for targeted therapy in young vs. 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.

Abstract

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. 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: PPARγ increases klotho levels, and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/ Wnt5A crosstalk, in vitro and in vivo, and the implications of that for targeted therapy in young vs. 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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2017
Deposited On:09 Mar 2017 13:17
Last Modified:16 Jun 2017 01:02
Publisher:American Association for Cancer Research
ISSN:1078-0432
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1078-0432.CCR-17-0201
PubMed ID:28232477

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