Pathophysiological mechanisms of death resistance in colorectal carcinoma

Table 1 Alteration of apoptotic and necroptotic regulators in human colon cancers

Classification	Molecule	Expression in cancer tissues	Ref.
Bcl-2 family	Bcl-XL	Increased	[56]
IAP family	cFLIP	Increased	[57]
	cIAP2	Increased	[59,60]
	survivin	Increased	[55,61]
	XIAP	Increased	[58]
RIP kinase family	RIPK1/RIPK3	Decreased	[62]

IAP: Inhibitor of apoptosis protein; FLIP: FLICE-like inhibitory protein; XIAP: X-linked IAP; RIP: Receptor-interacting protein.

Table 2 Signaling pathways for modulation of apoptotic regulators in cancer

Pathway	Observation in experimental models	Ref.
PI3K/Akt	Increase of Bcl-2, Bcl-XL and survivin expression in colon cancer cell lines (SW480, SW620, HCT116, and HT29)	[74,75]
	Inactivation of BAD by phosphorylation in colon cancer cell lines (HT29 and H508)	[76,77]
	Decreased expression of Bim and inactivation of Bax in colon cancer cell lines (HCT116 and DLD1), and increase of tumor growth in xenograft models	[78]
MEK/ERK	Phosphorylation and stabilization of Bcl-2 in colon cancer cell lines (HCT116 and HT29) for increase of anoikis, and promotion of metastasis in xenograft models	[80]
	Decreased expression of Bim and inactivation of Bax in colon cancer cell lines (HCT116 and DLD1), and increase of tumor growth in xenograft models	[78]
	Suppression of PUMA expression and activity in colon cancer cell lines (Lovo and SW1116)	[73]
	Dowregulation of XAF1 and upregulation of XIAP in colon cancer cell lines (HCT116, Lovo, DLD1, and SW1116)	[82]
IKK/IκB/NFκB	Induction of cIAP-2 expression in colon cancer cell lines (Caco-2, HCT116, KM20, and KM12C)	[91]
	Increase of Bcl-2, Bcl-XL, and cFLIP in colon cancer cell lines (COLO205 and HCT116)	[92]
HIF	Binding to hypoxia-responsive element of the Bid promoter in colon cancer cells (SW480) for Bid downregulation	[94]
	Binding to hypoxia-responsive element of the survivin promoter in breast cancer cells (MCF-7) for survivin upregulation	[93]

PI3K: Phosphatidylinositide 3-kinase; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; NFκB: Nuclear factor kappa B; IκB: Inhibitor of NFκB; IKK: IκB kinase; HIF: Hypoxia-inducible factor.

Table 3 Glucose-dependent mechanisms in death resistance of colon cancer

Classification	Molecule	Expression and mechanism	Ref.
Glucose uptake
Transporters	GLUT1	Abnormal expression of GLUT1 in colon cancer	[128,129]
		Hypoxia-induced expression of GLUT1 by HIF-1 binding to the GLUT1 promoter	[96,131,132]
		GLUT1-mediated glucose uptake promoted drug resistance in colon cancer cells	[136]
	GLUT3,4	Abnormal expression of GLUT3,4 in colon cancer	[19,27,130]
	SGLT1	Abnormal expression of SGLT1 in colon cancer	[27,115]
		Stabilization of membrane SGLT1 expression is dependent on EGFR in a kinase-independent mechanism	[117,134]
Glucose metabolism
Enzymes	PK	Upregulation of PKM2 isoform in chemoresistant cancer cells	[132]
	PDK-1	PDK-1 as a novel Wnt target gene improved colon cancer cell survival via enhancement of glycolysis	[142]
	PDK-3	HIF1-mediated upregulation of PDK-3 inhibited mitochondrial phosphorylation and promoted drug resistance	[143]
	HK, GAPDH	HIF1-dependent transcriptional upregulation	[45,96]
	PDH	Decreased expression in colon cancer cells	[141]
Carriers	MPC	Reduction of MPC activity promoted glycolysis and maintenance of stemness properties	[144]
Products	ATP	Elevation of intracellular ATP promoted cancer cell survival and induced drug resistance	[145,146]
	Pyruvate	Pyruvate prevented hypoxia-induced necroptosis through suppression of mitochondrial free radicals in an ATP-independent mechanism	[19]

GLUT: Glucose transporter; SGLT1: Sodium-dependent glucose transporter 1; EGFR: Epidermal growth factor receptor; PK: Pyruvate kinase; PDK: Pyruvate dehydrogenase kinase; HK: Hexokinase; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; PK: Pyruvate kinase; PDH: Pyruvate dehydrogenase; MPC: Mitochondrial pyruvate carrier.