Session: SUN 292-302-Breast & Prostate Cancer
Poster Board SUN-301
Vladislava Paharkova, Kuk-Wha Lee
Division of Pediatric Endocrinology, Mattel Children’s Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA
IGFBP-3 is a tumor suppressor implicated in prostate cancer (CaP) as a regulator of IGF bioavailability; mediator of anti-growth and senescence signals; IGF-independent induction of apoptosis; and an anti-angiogenic agent. We have demonstrated that genetic loss of IGFBP-3 increases the incidence of metastasis in a mouse model of c-Myc driven CaP. IGFBP-3KO:Myc tumors have increased invasiveness and show 60-fold downregulation of SM22. SM22 (transgelin) is an actin filament-associated tumor suppressor and its decrease in CaP, breast, colon and lung cancer enhances tumorigenicity and metastasis.
Because of our experimental observations that IGFBP-3 regulates SM22 expression and the reported by others direct interaction between SM22 and IGF1Rβ, we sought to further elucidate the anti-metastatic interactions between IGFBP-3 and SM22 in 22Rv1 CaP cells – an in vitro cancer model expressing IGFBP-3.
SM22 knockdown (KD) results in 9-fold increase in invasiveness, as measured by Matrigel invasion assay, which is reversed by IGFBP-3 supplementation in a dose- dependent manner. Recombinant IGFBP-3 addition induced SM22 protein expression in wild type and SM22 KD 22Rv1 cells 3- and 6.4-fold respectively, as revealed by Western Blot. Transient KD of SM22 leads to 3.3-fold decrease in IGFBP-3 expression 24h post transfection. Kinetics of SM22 post-transcriptional gene silencing revealed cross-regulation of protein expression between IGFBP-3 and SM22.
Since metastasis is the major cause for mortality in patients with CaP, the interactions between IGFBP-3 and SM22 in inhibition of cell invasion in vitro, combined with metastasis observations in vivo strengthens IGFBP-3’s significance as a major checkpoint for cancer progression and a focus for therapeutic cancer targeting.
Nothing to Disclose: VP, KWL
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