**2.3. Abnormal cross talk of autophagy and apoptosis**

Autophagy is the process of self-digestion and degradation of proteins, organelles, and cell to obtain essential elements and energy for cell survival. Under normal physiological conditions, autophagy allows the cells to maintain homeostasis by transporting damaged or senescent substances into the lysosome, preventing the intercellular accumulation of toxic or carcinogenic substances and inhibiting cell carcinogenesis. However, in the tumor microenvironment, autophagy supplies nutrients to cancer cells and promotes tumor growth. The cross talk between autophagy and apoptosis contributes to cell viability (**Figure 2**). Apoptosis regulates autophagy either through specific apoptotic protein regulation or by caspase activation, while autophagy regulates apoptosis through: (1) specific autophagy protein regulation; (2) caspase activation (autophagosome required); (3) autophagic degradation (both autophagosome and lysosome required) and mutual signal pathways [28].

caspase 8 may fail to trigger the downstream cascade of apoptosis. Furthermore, Beclin-1 is mediated by caspases; mutant D133A+D146A Beclin-1 has been reported to be resistant to chemotherapy [29]. Third, autophagic degradation downregulates apoptosis. In normal condition, starving cells accelerate apoptosis. However, the apoptosis is attenuated in tumors because the neighboring cancer cells degraded by autophagy provide nutrient and ATP for tumorigenesis. Fourth, malfunctioned signal pathways hinder the cell death process. The p53 protein can be regulated by AMPK pathway and degraded by chaperone-mediated autophagy. In p53-induced apoptosis, the downregulation of damage-regulated autophagy modulator (DRAM) mRNA has been observed in tumor with wild-type; the deficiency of DRAM promotes cell survival [30]. Han et al. [31] have reported that suberoylanilide hydroxamic acid (SAHA) may promote autophagy by stimulating TRAIL-R2-CTSB via AKT pathway.

complex is recruited by autophagosome. (3) Autophagic degradation downregulates apoptosis.

**Figure 2.** Abnormal apoptosis-autophagy cross talk. (1) The unusual autophagy proteins would result in apoptosis evasion. In abnormal apoptotic cells, fewer ATG5 translocate and interact with Bcl-XL in mitochondria, reducing the release of cytochrome C; meanwhile, the dwindling ATG12 binds to Bcl-2 and Mcl-1 results in the decrease of caspase activation. (2) Aberrant activation of caspases leads to cell immortality. For example, caspase 8 activated by DISC-like

Role of Apoptosis in Cancer Resistance to Chemotherapy

http://dx.doi.org/10.5772/intechopen.80056

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In clinical treatments, the principle to treat drug-resistant cancer is targeting the specific target with the coordinated agent. However, the strategy is idealized since drug-resistant cancer usually involves multiple signaling pathways as well as multiple targets, and the contributions of each target is hard to be calculated. Therefore, treating drug-resistant cancer with the drugs against

**3. Possible approaches to overcoming cancer resistance**

The abnormal apoptosis-autophagy cross talk helps cell death evasion. First, the unusual autophagy proteins would result in apoptosis evasion. In normal apoptotic cells, autophagosome with the regulation of autophagy protein 9 (ATG9), ATG16L1, ATG5, and ATG12 shows a pro-apoptotic effect. However, in abnormal apoptotic cells, less ATG5 translocation and interaction with Bcl-XL in mitochondria reduces cytochrome C release; meanwhile, the dwindling binding of ATG12 to Bcl-2 and Mcl-1 decreases caspase activation [28]. In addition, the Beclin-1 interacting UV radiation resistance-associated gene (UVRAG) shows an inhibitory effect on apoptosis by binding to Bax [29]. Second, aberrant activations of caspases lead to the longevity of cancer cells. For example, caspase 8 is recruited by autophagosome, and caspase 8/RIPK1 is important for apoptosis-autophagy cross talk [28]. The inefficient activated

outer membrane of mitochondria, reducing the pro-apoptotic effect [23]. Furthermore, mouse double minute 2 homolog (MDM2) has also been found to play a pivotal role in the inhibition of p53-mediated apoptosis by negative regulation. In cancer cells, the increase of MDM2 tran-

NF-κB pathway, one of the highly conserved signal pathways of activating gene transcription, takes complicated apoptotic effects in different cells. Activated NF-κB improves the transcription level of survivin, Bcl-2, Bcl-XL, and XIAP, resulting in resistance to the chemotherapeutic pro-apoptotic signals [5]. However, NF-κB renders pro-apoptotic effect through upregulating caspase 4 in Fas-induced neuroblastoma cell apoptosis [25]. In addition, NF-κB upregulates

PI3/AKT pathway mediates the survival signals in cancer cells. Akt is correlated to phosphorylation of diverse signal molecules and has a profound effect on cell survival, cell cycle progression, cell growth, and metabolism. The overexpression and overactivation of Akt have been observed in malignant tumors. For example, Zheng [5] has revealed that the paclitaxel-resistance developed in NSCLC can be ascribed to Akt-1 overexpression and Akt-2 gene amplification. In addition, Akt promotes the phosphorylation of Bad on Ser136/Ser112, leading to the suppression of apoptosis [26]. Akt phosphorylates Forkhead-box Class O (FoxO), a protein family governing a line of apoptotic gene transcription in PI3K/Akt pathway. The phosphorylated FoxO binds with

Autophagy is the process of self-digestion and degradation of proteins, organelles, and cell to obtain essential elements and energy for cell survival. Under normal physiological conditions, autophagy allows the cells to maintain homeostasis by transporting damaged or senescent substances into the lysosome, preventing the intercellular accumulation of toxic or carcinogenic substances and inhibiting cell carcinogenesis. However, in the tumor microenvironment, autophagy supplies nutrients to cancer cells and promotes tumor growth. The cross talk between autophagy and apoptosis contributes to cell viability (**Figure 2**). Apoptosis regulates autophagy either through specific apoptotic protein regulation or by caspase activation, while autophagy regulates apoptosis through: (1) specific autophagy protein regulation; (2) caspase activation (autophagosome required); (3) autophagic degradation (both autophago-

The abnormal apoptosis-autophagy cross talk helps cell death evasion. First, the unusual autophagy proteins would result in apoptosis evasion. In normal apoptotic cells, autophagosome with the regulation of autophagy protein 9 (ATG9), ATG16L1, ATG5, and ATG12 shows a pro-apoptotic effect. However, in abnormal apoptotic cells, less ATG5 translocation and interaction with Bcl-XL in mitochondria reduces cytochrome C release; meanwhile, the dwindling binding of ATG12 to Bcl-2 and Mcl-1 decreases caspase activation [28]. In addition, the Beclin-1 interacting UV radiation resistance-associated gene (UVRAG) shows an inhibitory effect on apoptosis by binding to Bax [29]. Second, aberrant activations of caspases lead to the longevity of cancer cells. For example, caspase 8 is recruited by autophagosome, and caspase 8/RIPK1 is important for apoptosis-autophagy cross talk [28]. The inefficient activated

scription and p53 ubiquitination attenuates p53-mediated apoptosis [24].

14-3-3, stays in the cytoplasm, and fails to execute transcription in nucleus [27].

**2.3. Abnormal cross talk of autophagy and apoptosis**

some and lysosome required) and mutual signal pathways [28].

pro-survival genes via Akt activation.

130 Current Understanding of Apoptosis - Programmed Cell Death

**Figure 2.** Abnormal apoptosis-autophagy cross talk. (1) The unusual autophagy proteins would result in apoptosis evasion. In abnormal apoptotic cells, fewer ATG5 translocate and interact with Bcl-XL in mitochondria, reducing the release of cytochrome C; meanwhile, the dwindling ATG12 binds to Bcl-2 and Mcl-1 results in the decrease of caspase activation. (2) Aberrant activation of caspases leads to cell immortality. For example, caspase 8 activated by DISC-like complex is recruited by autophagosome. (3) Autophagic degradation downregulates apoptosis.

caspase 8 may fail to trigger the downstream cascade of apoptosis. Furthermore, Beclin-1 is mediated by caspases; mutant D133A+D146A Beclin-1 has been reported to be resistant to chemotherapy [29]. Third, autophagic degradation downregulates apoptosis. In normal condition, starving cells accelerate apoptosis. However, the apoptosis is attenuated in tumors because the neighboring cancer cells degraded by autophagy provide nutrient and ATP for tumorigenesis. Fourth, malfunctioned signal pathways hinder the cell death process. The p53 protein can be regulated by AMPK pathway and degraded by chaperone-mediated autophagy. In p53-induced apoptosis, the downregulation of damage-regulated autophagy modulator (DRAM) mRNA has been observed in tumor with wild-type; the deficiency of DRAM promotes cell survival [30]. Han et al. [31] have reported that suberoylanilide hydroxamic acid (SAHA) may promote autophagy by stimulating TRAIL-R2-CTSB via AKT pathway.
