The effects of growth hormone on therapy resistance in cancer

Abstract

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.

Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma

“…Conversely, melanoma with dysfunctional melanosomal and melanogenic machinery have increased cisplatin sensitivity [27]. One of the most critical effects of the melanoma oncogene MITF is therefore in therapy resistance—a phenomenon in cancer cells which also strongly implicates GH action [14], especially in metastatic (stage IV) melanoma [21], which also displays the highest GHR expression in the NCI60 panel [6] of 60 human tumor cell lines of eleven different cancer types. Although the exogenous growth factors bFGF, EGF, and HGF have been found to not affect V600E-BRAF melanoma viability or response to BRAF-inhibitors [60], we have previously reported that GHR inhibition sensitizes human melanoma to the BRAF inhibitor vemurafenib by suppressing ABC-transporter-mediated clearance of vemurafenib [21].…”

“…Increased GH responsiveness was identified by immunohistochemical studies targeting GHR on melanoma patient-derived paraffin samples [11]. A large body of research in the last 20 years has implicated GH action in the regulation of multiple oncogenic processes such as proliferation, migration, invasion, anchorage-independent growth, as well as resistance to chemo- and targeted therapy in human tumors [12,13,14]. However, the essential molecular underpinnings of these GH-regulated oncogenic processes are only recently coming to light.…”

Growth hormone in the tumor microenvironment

“…However, TME may modulate responses to cytotoxic therapy, and GH, as a part of TME, may contribute to this process. GH effects on therapy resistance to cancer has been well described (80). Here, we elaborate on additional aspects of GH actions contributing to its effects on treatment resistance.…”

“…GH may also impact chemotherapy resistance via its effects on multi-drug efflux pumps, which transport xenobiotics out of the cytoplasm (80). For example, GH expression in four different human melanoma cell lines upregulated expression of multiple ABC-family multi-drug efflux pumps, rendering cells resistant to chemotherapy (84).…”

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases

“…A growing number of studies implicate GH also in development of therapeutic resistance in a variety of human cancers (322). Both JAK2-and Lyn-initiated pathways activate, upon anti-cancer treatment, many different systems that upregulate ABC-multidrug efflux pumps (ABCG2), block apoptosis, DNA repair (p53), and pro-apoptotic molecules (Bax, PPARg), suppresses caspase activation, and induce EMT and markers of stemness like ALDH1, NANOG, and CD24.…”