Tobacco carcinogen–induced production of GM-CSF activates CREB to promote pancreatic cancer

Supriya Srinivasan, Tulasigeri Totiger, Chanjuan Shi, Jason Castellanos, Purushottam Lamichhane, Austin R. Dosch, Fanuel Messaggio, Nilesh Kashikar, Kumaraswamy Honnenahally, Yuguang Ban, Nipun Merchant, Michael Vansaun, Nagaraj Nagathihalli

Research output: Contribution to journalArticle

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Abstract

Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF–mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC. Significance: These findings identify GM-CSF-induced CREB as a driver of pancreatic cancer in smokers and demonstrate the therapeutic potential of targeting CREB to reduce PDAC tumor growth.

Original languageEnglish (US)
Pages (from-to)6146-6158
Number of pages13
JournalCancer Research
Volume78
Issue number21
DOIs
StatePublished - Nov 1 2018

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Cyclic AMP Response Element-Binding Protein
Granulocyte-Macrophage Colony-Stimulating Factor
Pancreatic Neoplasms
Tobacco
Adenocarcinoma
Carcinoma in Situ
Tumor Burden
Neoplasms
Smoking
Macrophages
Butanones
Cell Line
Nitrosamines
Regulatory T-Lymphocytes
Growth
Pancreas
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tobacco carcinogen–induced production of GM-CSF activates CREB to promote pancreatic cancer. / Srinivasan, Supriya; Totiger, Tulasigeri; Shi, Chanjuan; Castellanos, Jason; Lamichhane, Purushottam; Dosch, Austin R.; Messaggio, Fanuel; Kashikar, Nilesh; Honnenahally, Kumaraswamy; Ban, Yuguang; Merchant, Nipun; Vansaun, Michael; Nagathihalli, Nagaraj.

In: Cancer Research, Vol. 78, No. 21, 01.11.2018, p. 6146-6158.

Research output: Contribution to journalArticle

Srinivasan, S, Totiger, T, Shi, C, Castellanos, J, Lamichhane, P, Dosch, AR, Messaggio, F, Kashikar, N, Honnenahally, K, Ban, Y, Merchant, N, Vansaun, M & Nagathihalli, N 2018, 'Tobacco carcinogen–induced production of GM-CSF activates CREB to promote pancreatic cancer', Cancer Research, vol. 78, no. 21, pp. 6146-6158. https://doi.org/10.1158/0008-5472.CAN-18-0579
Srinivasan S, Totiger T, Shi C, Castellanos J, Lamichhane P, Dosch AR et al. Tobacco carcinogen–induced production of GM-CSF activates CREB to promote pancreatic cancer. Cancer Research. 2018 Nov 1;78(21):6146-6158. https://doi.org/10.1158/0008-5472.CAN-18-0579
Srinivasan, Supriya ; Totiger, Tulasigeri ; Shi, Chanjuan ; Castellanos, Jason ; Lamichhane, Purushottam ; Dosch, Austin R. ; Messaggio, Fanuel ; Kashikar, Nilesh ; Honnenahally, Kumaraswamy ; Ban, Yuguang ; Merchant, Nipun ; Vansaun, Michael ; Nagathihalli, Nagaraj. / Tobacco carcinogen–induced production of GM-CSF activates CREB to promote pancreatic cancer. In: Cancer Research. 2018 ; Vol. 78, No. 21. pp. 6146-6158.
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abstract = "Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF–mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC. Significance: These findings identify GM-CSF-induced CREB as a driver of pancreatic cancer in smokers and demonstrate the therapeutic potential of targeting CREB to reduce PDAC tumor growth.",
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AU - Lamichhane, Purushottam

AU - Dosch, Austin R.

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AU - Kashikar, Nilesh

AU - Honnenahally, Kumaraswamy

AU - Ban, Yuguang

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AU - Vansaun, Michael

AU - Nagathihalli, Nagaraj

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