Metastasis of Colon Carcinoma Cells Depends on a TGF-beta Signaling Protein

Cancer researchers have linked the transforming growth factor-beta (TGF-beta) receptor-interacting protein km23-1 to the ability of human colon carcinoma cells to migrate and metastasize.

Previous studies had shown that km23-1, a member of an ancient superfamily of NTPase-regulatory proteins, was a TGF-beta receptor-interacting protein that played an important role in TGF-beta signaling.

To further elucidate the function of km23-1, investigators at the Pennsylvania State College of Medicine (Hershey, USA) identified its novel protein interacting partners by using tandem affinity purification (TAP) and tandem mass spectrometry (MS).

Results published in the November 23, 2012, issue of the journal Biochemical and Biophysical Research Communications revealed that km23-1 interacted with a class of proteins involved in actin-based cell motility and modulation of the actin cytoskeleton. Km23-1 modulated the formation of a highly organized stress fiber network. Knockdown (KD) of km23-1 decreased RhoA activation in Mv1Lu epithelial cells. RhoA (Ras homolog gene family, member A) is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. This protein is essential for the signaling function of the Rho GTPase complex. Previous studies have shown that in breast cancer increased RhoA activity stimulated cancer cell invasiveness and spreading, while RhoA deficiency suppressed cancer growth and progression. In addition to its role in breast cancer, imbalance in Rho GTPase activity has been implicated in other human diseases, including various cancers and neurological disorders.

The results of the current study demonstrated for the first time, according to the investigators, that depletion of km23-1 inhibited cell migration of human colon carcinoma cells (HCCCs) in wound-healing assays.

"Cell migration is an important aspect of the process of a tumor spreading," said senior author Dr. Kathleen Mulder, professor of biochemistry and molecular biology at the Pennsylvania State College of Medicine. "Changes in this process transform tumor cells from local, noninvasive, confined cells to the migrating, metastatic cancer cells. By knowing that RhoA activity was decreased when km23-1 was reduced, we infer that km23-1 is needed for the regulation of these switches and has a role in cell movement. By inhibiting km23-1, you inhibit events that contribute to the cells spreading to other parts of the body."

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Pennsylvania State College of Medicine