FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells.

Host immune peptides, including cathelicidins, have been reported to possess anticancer properties. We previously reported that LL-37, the only cathelicidin in humans, suppresses the development of colon cancer. In this study, the potential anticancer effect of FK-16, a fragment of LL-37 corresponding to residues 17 to 32, on cultured colon cancer cells was evaluated. FK-16 induced a unique pattern of cell death, marked by concurrent activation of caspase-independent apoptosis and autophagy. The former was mediated by the nuclear translocation of AIF and EndoG whereas the latter was characterized by enhanced expression of LC3-I/II, Atg5 and Atg7 and increased formation of LC3-positive autophagosomes. Knockdown of Atg5 or Atg7 attenuated the cytotoxicity of FK-16, indicating FK-16-induced autophagy was pro-death in nature. Mechanistically, FK-16 activated nuclear p53 to upregulate Bax and downregulate Bcl-2. Knockdown of p53, genetic ablation of Bax, or overexpression of Bcl-2 reversed FK-16-induced apoptosis and autophagy. Importantly, abolition of AIF/EndoG-dependent apoptosis enhanced FK-16-induced autophagy while abolition of autophagy augmented FK-16-induced AIF-/EndoG-dependent apoptosis. Collectively, FK-16 induces caspase-independent apoptosis and autophagy through the common p53-Bcl-2/Bax cascade in colon cancer cells. Our study also uncovered previously unknown reciprocal regulation between these two cell death pathways.

Epidermal growth factor-induced esophageal cancer cell proliferation requires transactivation of beta-adrenoceptors.

Unchecked mitogenic signals due to the overexpression of epidermal growth factor (EGF) and its receptor (EGFR) is implicated in the promotion and progression of cancer. In addition, beta-adrenoceptor is involved in the control of cancer cell proliferation. This study sought to elucidate whether a functional connection exists between these two disparate receptor systems. EGF was used to stimulate HKESC-1 cells, an esophageal squamous cancer cell line, in which beta-adrenoceptor activity was monitored by measuring intracellular cAMP levels in the absence or presence of beta-adrenoceptor antagonists. Results showed that EGF significantly increased cAMP levels and cell proliferation, both of which were attenuated by atenolol [(+)-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]benzeneacetamide] or ICI 118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol], which are antagonists for the beta-adrenoceptor. Further mechanistic investigation revealed that the cellular release of epinephrine and the expression of its synthesizing enzyme tyrosine hydroxylase were induced by EGF. The expression of beta(1)-adrenoceptor and the downstream signal transducer protein kinase A were also up-regulated. In this connection, AG1478 [4-(3-chloroanilino)-6,7-dimethoxyquinazoline], an EGFR tyrosine kinase inhibitor, abrogated all these EGF-elicited alteration. Collectively, this study demonstrates that beta-adrenergic signaling could be up-regulated at multiple levels upon EGFR activation to mediate the mitogenic signals in esophageal cancer cells. This novel finding not only unveils the sinister liaison between EGFR and beta-adrenoceptors but also sheds new light on the purported therapeutic use of beta-adrenoceptor antagonists in the treatment of esophageal cancer.