Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation

Samudra K. Dissanayake, Purevdorj B. Olkhanud, Michael P. O'Connell, Arnell Carter, Amanda D. French, Tura C. Camilli, Chineye D. Emeche, Kyle J. Hewitt, Devin T. Rosenthal, Poloko D. Leotlela, Michael S. Wade, Sherry W. Yang, Larry Brant, Brian J. Nickoloff, Jane L. Messina, Arya Biragyn, Keith S. Hoek, Dennis D. Taub, Dan L. Longo, Vernon K. SondakStephen M. Hewitt, Ashani T. Weeraratna

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Abstract

There are currently no effective therapies for metastatic melanoma and targeted immunotherapy results in the remission of only a very small percentage of tumors. In this study, we show that the noncanonical Wnt ligand, Wnt5A, can increase melanoma metastasis in vivo while down-regulating the expression of tumor-associated antigens important in eliciting CTL responses (e.g., MART-1, GP100, and tyrosinase). Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. Downstream targets such as PAX3, MITF, and MART-1 were also affected by Wnt5A treatment or knockdown. Staining of a melanoma tissue array also highlighted the inverse relationship between MART-1 and Wnt5A expression. PKC activation by phorbol ester mimicked Wnt5A effects, and Wnt5A treatment in the presence of STAT3 or PKC inhibitors did not lower MART-1 levels. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma.

Original languageEnglish (US)
Pages (from-to)10205-10214
Number of pages10
JournalCancer Research
Volume68
Issue number24
DOIs
StatePublished - Dec 15 2008

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STAT3 Transcription Factor
Neoplasm Antigens
Melanoma
Phosphorylation
Immunotherapy
Monophenol Monooxygenase
Phorbol Esters
Transcriptional Activation
Therapeutics
Staining and Labeling
Neoplasm Metastasis
Ligands
Antigens
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dissanayake, S. K., Olkhanud, P. B., O'Connell, M. P., Carter, A., French, A. D., Camilli, T. C., ... Weeraratna, A. T. (2008). Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation. Cancer Research, 68(24), 10205-10214. https://doi.org/10.1158/0008-5472.CAN-08-2149

Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation. / Dissanayake, Samudra K.; Olkhanud, Purevdorj B.; O'Connell, Michael P.; Carter, Arnell; French, Amanda D.; Camilli, Tura C.; Emeche, Chineye D.; Hewitt, Kyle J.; Rosenthal, Devin T.; Leotlela, Poloko D.; Wade, Michael S.; Yang, Sherry W.; Brant, Larry; Nickoloff, Brian J.; Messina, Jane L.; Biragyn, Arya; Hoek, Keith S.; Taub, Dennis D.; Longo, Dan L.; Sondak, Vernon K.; Hewitt, Stephen M.; Weeraratna, Ashani T.

In: Cancer Research, Vol. 68, No. 24, 15.12.2008, p. 10205-10214.

Research output: Contribution to journalArticle

Dissanayake, SK, Olkhanud, PB, O'Connell, MP, Carter, A, French, AD, Camilli, TC, Emeche, CD, Hewitt, KJ, Rosenthal, DT, Leotlela, PD, Wade, MS, Yang, SW, Brant, L, Nickoloff, BJ, Messina, JL, Biragyn, A, Hoek, KS, Taub, DD, Longo, DL, Sondak, VK, Hewitt, SM & Weeraratna, AT 2008, 'Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation', Cancer Research, vol. 68, no. 24, pp. 10205-10214. https://doi.org/10.1158/0008-5472.CAN-08-2149
Dissanayake, Samudra K. ; Olkhanud, Purevdorj B. ; O'Connell, Michael P. ; Carter, Arnell ; French, Amanda D. ; Camilli, Tura C. ; Emeche, Chineye D. ; Hewitt, Kyle J. ; Rosenthal, Devin T. ; Leotlela, Poloko D. ; Wade, Michael S. ; Yang, Sherry W. ; Brant, Larry ; Nickoloff, Brian J. ; Messina, Jane L. ; Biragyn, Arya ; Hoek, Keith S. ; Taub, Dennis D. ; Longo, Dan L. ; Sondak, Vernon K. ; Hewitt, Stephen M. ; Weeraratna, Ashani T. / Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation. In: Cancer Research. 2008 ; Vol. 68, No. 24. pp. 10205-10214.
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AU - Dissanayake, Samudra K.

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AU - Carter, Arnell

AU - French, Amanda D.

AU - Camilli, Tura C.

AU - Emeche, Chineye D.

AU - Hewitt, Kyle J.

AU - Rosenthal, Devin T.

AU - Leotlela, Poloko D.

AU - Wade, Michael S.

AU - Yang, Sherry W.

AU - Brant, Larry

AU - Nickoloff, Brian J.

AU - Messina, Jane L.

AU - Biragyn, Arya

AU - Hoek, Keith S.

AU - Taub, Dennis D.

AU - Longo, Dan L.

AU - Sondak, Vernon K.

AU - Hewitt, Stephen M.

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