Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma

Subramani, Ramadevi; Lopez-Valdez, Rebecca; Salcido, Alyssa; Boopalan, Thiyagarajan; Arumugam, Arunkumar; Nandy, Sushmita; Lakshmanaswamy, Rajkumar

doi:10.1038/emm.2014.61

Cited by 34 publications

(32 citation statements)

References 47 publications

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“…In addition, Sustarsic et al (2013) has reported that melanoma express the highest level of GHR among several human cancer cells of NCI60 panel (US National Cancer Institute’s Development Therapeutics Program). Other studies have also shown that targeting GHR can control cancer metastasis, such as pancreatic cancer [40]. In this study, we found that GHR down-regulation reduced lung metastasis of melanoma cells (Fig.…”

Section: Discussionsupporting

confidence: 73%

Growth hormone is increased in the lungs and enhances experimental lung metastasis of melanoma in DJ-1 KO mice

et al. 2016

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BackgroundGrowth hormone (GH) mainly serves an endocrine function to regulate somatic growth, but also serves an autocrine function in lung growth and pulmonary function. Several recent studies have demonstrated the role of autocrine GH in tumor progression in some organs. However, it is not clear whether excessive secretion of GH in the lungs is related to pulmonary nodule formation.MethodsFirstly, the lung tissues dissected from mice were used for Western blotting and PCR measurement. Secondly, the cultured cells were used for examining effects of GH on B16F10 murine melanoma cells. Thirdly, male C57BL/6 mice were intravenously injected with B16F10 cells and then subcutaneously injected with recombinant GH twice per week for three weeks. Finally, stably transfected pool of B16F10 cells with knockdown of growth hormone receptor (GHR) was used to be injected into mice.ResultsWe found that expression of GH was elevated in the lungs of DJ-1 knockout (KO) mice. We also examined the effects of GH on the growth of cultured melanoma cells. The results showed that GH increased proliferation, colony formation, and invasive capacity of B16F10 cells. In addition, GH also increased the expression of matrix metalloproteinases (MMPs) in B16F10 cells. Administration of GH in vivo enhanced lung nodule formation in C57/B6 mice. Increased lung nodule formation in DJ-1 KO mice following intravenous injection of melanoma cells was inhibited by GHR knockdown in B16F10 cells.ConclusionsThese results indicate that up-regulation of GH in the lungs of DJ-1 KO mice may enhance the malignancy of B16F10 cells and nodule formation in pulmonary metastasis of melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2898-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 73%

Growth hormone is increased in the lungs and enhances experimental lung metastasis of melanoma in DJ-1 KO mice

et al. 2016

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“…Blocking GH signaling by siRNA-mediated GHR knock-down (GHRKD) reversed the effects [132] . Consistent results of GH induced EMT were also observed in GHR-expressing pancreatic ductal adenocarcinoma cells following exogenous GH treatment or GHRKD [107] . B2036 was reported to also inhibit GH-induced EMT, tumor invasion and anchorage-independent cell growth in vivo in endometrial cancer [133] .…”

Section: Emtsupporting

confidence: 70%

“…Bogazzi et al [106] had proposed another mechanism of the anti-apoptotic effects of GH where it blocks the expression of proapoptotic PPARγ and Bax in colon cancer cells [106] . This survival advantage of tumors bestowed upon by GH to evade the DNA damaging effects of therapy and avoid apoptosis, were also reported in pancreatic cancer [107] , and breast cancer [108][109][110] . Therefore, there appears to be a consensus over the anti-apoptotic effects of GH which is harnessed by the proliferative tumor cells; while the details of molecular events converging to the net effect of escaping cell death are overlapping and still emerging.…”

Section: Deregulated Apoptosismentioning

confidence: 68%

“…Therefore, increased collagen deposition as well as increased collagen breakdown are fundamental methods of ECM remodeling [190] . GH is known to upregulate both collagen synthesis in human subjects [194] and to increase expression of collagen degrading and TGF-activating MMPs [107,133] in tumors. Additionally, autocrine GH expressing breast cancer cells show increased blood and lymphatic microvessel infiltration in tumor xenografts in vivo, due to elevated VEGF signaling [87] .…”

Section: Mechanisms Overlapping Gh-action and Cancer Therapy Resistancementioning

confidence: 99%

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The effects of growth hormone on therapy resistance in cancer

Basu¹,

Kopchick²

2019

CDR

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Pituitary derived and peripherally produced growth hormone (GH) is a crucial mediator of longitudinal growth, organ development, metabolic regulation with tissue specific, sex specific, and age-dependent effects. GH and its cognate receptor (GHR) are expressed in several forms of cancer and have been validated as an anti-cancer target through a large body of in vitro, in vivo and epidemiological analyses. However, the underlying molecular mechanisms of GH action in cancer prognosis and therapeutic response had been sparse until recently. This review assimilates the critical details of GH-GHR mediated therapy resistance across different cancer types, distilling the therapeutic implications based on our current understanding of these effects.

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“…Our comprehensive computational analysis has predicted that several oncogenic signaling pathways important for induction of the EMT phenotype in various solid malignancies, such as WNT (52), hGH (53, 54), and TGFβ (14, 52), as well as downstream pathway modulators such as RAS (52), MAPK (52), JNK (52), PAK/p38 (52), and mTOR (52), were significantly upregulated among the SMAD4 -low tumors in both TCGA-HNSCC dataset and a subset of HPV-negative OSCC tumors obtained from GEO. These pro-survival signaling axes play a crucial role in cancer initiation, progression and maintenance, and may contribute to survival and promotion of cetuximab resistance via inhibition of apoptosis and induction of cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Ozawa

Ranaweera

Izumchenko

et al. 2017

Clinical Cancer Research

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Purpose We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design SMAD4 expression was assessed by immunohistochemistry in 130 newly diagnosed and 43 recurrent HNSCC patients. Correlative statistical analysis with clinicopathological data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of pro-survival and anti-apoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in a HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.

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Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma

Cited by 34 publications

References 47 publications

Growth hormone is increased in the lungs and enhances experimental lung metastasis of melanoma in DJ-1 KO mice

Growth hormone is increased in the lungs and enhances experimental lung metastasis of melanoma in DJ-1 KO mice

The effects of growth hormone on therapy resistance in cancer

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

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