Abstract
BackgroundPlatinum-containing anti-cancer drugs such as cisplatin are widely used for patients with various types of cancers, however, resistance to cisplatin is observed in some cases. Whereas we have recently reported that high dose UV-C (200 J/m²) induces colorectal cancer cell proliferation by desensitization of EGFR, which leads oncogenic signaling in these cells, in this study we investigated the combination effect of low dose cisplatin (10 μM) and low dose UV-C (10 J/m²) on cell growth and apoptosis in several human colorectal cancer cells, SW480, DLD-1, HT29 and HCT116.ResultsThe combination inhibited cell cycle and colony formation, while either cisplatin or UV-C alone had little effect. The combination also induced apoptosis in these cells. In addition, the combination caused the downregulation of EGFR and HER2. Moreover, UV-C alone caused the transient internalization of the EGFR, but with time EGFR recycled back to the cell surface, while cisplatin did not affect its localization. Surprisingly, the combination caused persistent internalization of the EGFR, which results in the lasting downregulation of the EGFR.ConclusionsThe combination of low dose cisplatin and low dose UV-C synergistically exerted anti-cancer effect by down-regulating RTK, such as EGFR and HER2. These findings may provide a novel strategy for the treatment of patients with colorectal cancer.
Highlights
Among the receptor tyrosine kinases (RTKs), the ErbB family, such as epidermal growth factor receptor (EGFR; ErbB1) or human epidermal growth factor receptor-2 (HER2; ErbB2) plays a pivotal role in regulating a number of cellular processes including cell proliferation, survival and migration [1], and dysregulation of Epidermal growth factor (EGF) receptor (EGFR) activity leads to tumorgenesis [2]
Whereas we recently reported the availability of UV-C alone (30 J/m2 and more) in human colorectal cancer cells, in which we showed that UV-C can evade these cells from oncogenic stimulation of EGF by decreasing the EGFR protein level [26], we investigated the combination use of low dose cisplatin and low dose UV-C on cell growth in human colorectal cancer cells (SW480, HT29, DLD-1 and HCT116) and found that the combination has synergistic effect on cell growth inhibition by down-regulating receptor tyrosine kinases, such as EGFR and Human epidermal growth factor receptor-2 (HER2)
Effects of cisplatin and/or UV-C on the apoptosis in human colorectal cancer cells We investigated the combination effect of cisplatin and UV-C on apoptosis by observing poly (ADP-ribose) polymerase (PARP) cleavage, since PARP is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death, indicating cell apoptosis [30]
Summary
Among the receptor tyrosine kinases (RTKs), the ErbB family, such as epidermal growth factor receptor (EGFR; ErbB1) or human epidermal growth factor receptor-2 (HER2; ErbB2) plays a pivotal role in regulating a number of cellular processes including cell proliferation, survival and migration [1], and dysregulation of EGFR activity leads to tumorgenesis [2]. We have previously reported that the blockade of EGF stimulation significantly suppressed colorectal cancer cell growth, suggesting that the EGFR pathway plays an important role in proliferation of these cells [4]. Since clinical and experimental evidences show a role for overexpression of the HER2 protein in the progression of human breast, ovarian, non-small cell lung [6] and colorectal cancer [7], HER2 may be a candidate target for receptor-targeted therapeutics. Whereas we have recently reported that high dose UV-C (200 J/m2) induces colorectal cancer cell proliferation by desensitization of EGFR, which leads oncogenic signaling in these cells, in this study we investigated the combination effect of low dose cisplatin (10 μM) and low dose UV-C (10 J/m2) on cell growth and apoptosis in several human colorectal cancer cells, SW480, DLD-1, HT29 and HCT116
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