Semaphorin 3C as a Therapeutic Target in Prostate and Other Cancers

Abstract

The semaphorins represent a large family of signaling molecules with crucial roles in neuronal and cardiac development. While normal semaphorin function pertains largely to development, their involvement in malignancy is becoming increasingly evident. One member, Semaphorin 3C (SEMA3C), has been shown to drive a number of oncogenic programs, correlate inversely with cancer prognosis, and promote the progression of multiple different cancer types. This report surveys the body of knowledge surrounding SEMA3C as a therapeutic target in cancer. In particular, we summarize SEMA3C's role as an autocrine andromedin in prostate cancer growth and survival and provide an overview of other cancer types that SEMA3C has been implicated in including pancreas, brain, breast, and stomach. We also propose molecular strategies that could potentially be deployed against SEMA3C as anticancer agents such as biologics, small molecules, monoclonal antibodies and antisense oligonucleotides. Finally, we discuss important considerations for the inhibition of SEMA3C as a cancer therapeutic agent.

Keywords: SEMA3C; cancer therapeutics; inhibitors; neuropilins; plexins; semaphorins.

Figure 1

High SEMA3C expression is associated with unfavourable prognosis in multiple cancers.

Figure 2

Androgen action. Testosterone circulates in the blood, enters prostate cells and is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase. Binding of DHT to the androgen receptor (AR) induces dissociation from heat-shock proteins (HSPs) and receptor phosphorylation. The AR is phosphorylated, dimerizes and translocates into the nucleus where it can bind to androgen-response elements in the promoter/enhancer regions of target genes. Activation (or repression) of target genes leads to biological responses including growth and survival. Drugs targeting various stages in the androgen/androgen receptor (AR) axis are shown. Dotted arrows represent multistep process, “T” arrows represents pathway inhibition.

Figure 3

Androgen receptor signaling in normal and malignant prostate cells. In normal prostate, the growth and survival of prostate epithelium depends on secreted soluble andromedins produced by the stromal cells in an androgen-dependent manner which diffuse across the basement membrane and act on epithelial receptors (above). Malignant transformation of normal prostatic epithelial cells is associated with a switch from a paracrine to an autocrine mechanism in androgen-stimulated growth (below). Androgens diffuse from blood circulation (straight green arrows) and bind to androgen receptors in cells that leads to production of andromedins that act in an autocrine or paracrine manner (curved green arrows).

Figure 4

SEMA3C signalling. Binding of SEMA3C to its receptors PLXNB1 and NRP1 triggers transactivation of multiple receptor tyrosine kinases such as EGFR, HER2 and MET. Arrows indicate protein interactions and signaling pathways.

Figure 5

Mechanisms of CRPC development. AR signalling can be activated via AR amplification or mutation to allow signalling despite castrate levels of androgens (hypersensitive pathway), AR variants mediate AR signaling in the absence of androgens, or through intratumoral steroidogenesis de novo or from adrenal androgens. Alternatively, AR signaling may be mediated via non-androgenic steroids (promiscuous pathway), while RTK signalling cascades allow tumor cells to survive without androgens (RTK crosstalk). In the absence of AR, survival can be enhanced through cell-intrinsic pathways, such as loss of phosphatase and tensin homologue (PTEN) or upregulation of anti-apoptotic Bcl-2 proteins (bypass pathway). Androgen independent prostate cancer stem cells undergo androgen independent self-renewal, persist after ADT, and seed tumor relapse. The potential role of SEMA3C in each resistance mechanism is described as shown. AR: androgen receptor, DHEA: dehydroepiandrosterone, DHT: dihydrotestosterone, RTK: receptor tyrosine kinase. Dotted red arrows indicate multi-step process, curved blue arrows indicate cell self-renewal and red solid arrows signify signaling pathways.